Fn3 domain-IFIH1 sirna conjugates and uses thereof

Abstract

The present disclosure relates to IFIH1-targeting siRNA molecules, and conjugates and compositions comprising the same, as well as methods of making and using the same.

Description

Attorney Docket No. ROO-037WO PATENTFN3 DOMAIN-IFIH1 SIRNA CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 760,291, filed February 19, 2025, U. S. Provisional Application No. 63 / 879,862, filed September 11, 2025, and U. S. Provisional Application No. 63 / 976,341, filed February 5, 2026, each of which is hereby incorporated by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 12, 2026, is named “ROO-037WO_SL. XML” and is 2,625,536 bytes in size.FIELD

[0003] The present embodiments relate to IF1H1 siRNA molecules that can be conjugated to fibronectin type III domains (FN3) and methods of making and using the molecules.BACKGROUND

[0004] Therapeutic nucleic acid molecules include small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides, ribozymes, plasmids, immune stimulating nucleic acids, antagomirs, antimirs, microRNA mimics, supermirs, U1 adaptors, aptamers, and more. Certain therapeutic nucleic acid molecules, such as siRNA and miRNA, downregulate intracellular levels of specific proteins through a process termed RNA interference (RNAi). Therapeutic applications of RNAi are extremely broad because a construct comprising siRNA or miRNA can be synthesized to have any nucleotide sequence directed against any target nucleic acid sequence (e.g., a gene or portion thereof, or an mRNA or portion thereof) that the construct can access. siRNA constructs are known to be able to specifically downregulate target proteins in both in vitro and in vivo models, such as through knockdown of mRNA encoding the target proteins.

[0005] However, there are challenges associated with siRNA constructs. These constructs are susceptible to nuclease digestion in plasma and are limited in their ability to gain access to intracellular compartments where they can bind the RNA-induced Silencing Complex- 1 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT(RISC), especially if administered systemically as free polynucleotides. To overcome these challenges, delivery systems such as lipid nanoparticles formed from cationic lipids with other lipid components (such as cholesterol and PEG lipids) and carbohydrates (such as GalNAc trimers) have been used, but these systems have not been as successful in efficient and / or effective delivery to targets in any tissues other than liver tissue. Five different siRNA-based therapeutics (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) have been approved by both American and European regulatory agencies with several others in early- and late-stage clinical trials, and the liver is the target tissue for all five therapeutics. An siRNA-based therapeutic targeting genes in other tissues or cell types has yet to be elucidated or approved.

[0006] Interferon induced with helicase C domain 1 (IFIH1), also known as MDA5, is a nucleic acid sensor protein found primarily in secondary lymphoid organs and which detects viral double stranded RNA (dsRNA). MDA5 acts to trigger the innate immune response and is a therapeutic target for autoimmune diseases, such as type 1 diabetes. It is encoded by the IFIH1 gene, and a number of gain-of-function polymorphisms of IFIH1 are associated with susceptibility to various autoimmune diseases, while minor allelic variants of IFIH1 are protective against such diseases. MDA5 also plays an important role in enhancing natural killer cell activity in fighting infection.

[0007] Overall, the MDA5 protein plays a critical role in mediating the antiviral response and development of autoimmunity. But while MDA5 represents an attractive therapeutic target, it has been considered an undruggable target due to difficulty of access, and lack of small molecule binding pockets in the encoded protein. What is needed are technologies, such as compositions and methods, that can successfully target IFIH1 and / or MDA5 expression or activity. The present embodiments fulfil these needs as well as others.SUMMARY

[0008] The present disclosure provides, among other things, technologies such as compositions for targeting IFIH1, and uses thereof. Without being bound by theory, the present disclosure contemplates that compositions and uses provided herein allow IFIH1 to be targeted for knockdown by siRNA.

[0009] Provided herein is a composition comprising an siRNA molecule comprising a sense strand and an antisense strand that targets IFIH1 gene, wherein: the sense strand comprises a nucleobase sequence of SEQ ID NO: 116, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 416; the sense strand comprises a nucleobase sequence of SEQ ID- 2 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTNO: 100, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 400; the sense strand comprises a nucleobase sequence of SEQ ID NO: 101, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 401; the sense strand comprises a nucleobase sequence of SEQ ID NO: 102, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 402; the sense strand comprises a nucleobase sequence of SEQ ID NO: 103, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 403; the sense strand comprises a nucleobase sequence of SEQ ID NO: 104, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 404; the sense strand comprises a nucleobase sequence of SEQ ID NO: 105, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 405; the sense strand comprises a nucleobase sequence of SEQ ID NO: 106, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 406; the sense strand comprises a nucleobase sequence of SEQ ID NO: 107, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 407; the sense strand comprises a nucleobase sequence of SEQ ID NO: 108, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 408; the sense strand comprises a nucleobase sequence of SEQ ID NO: 109, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 409; the sense strand comprises a nucleobase sequence of SEQ ID NO: 110, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 410; the sense strand comprises a nucleobase sequence of SEQ ID NO: 111, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 411; the sense strand comprises a nucleobase sequence of SEQ ID NO: 112, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 412; the sense strand comprises a nucleobase sequence of SEQ ID NO: 113, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 413; the sense strand comprises a nucleobase sequence of SEQ ID NO: 114, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 414; the sense strand comprises a nucleobase sequence of SEQ ID NO: 115, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 415; the sense strand comprises a nucleobase sequence of SEQ ID NO: 117, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 417; the sense strand comprises a nucleobase sequence of SEQ ID NO: 118, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 418; the sense strand comprises a nucleobase sequence of SEQ ID NO: 119, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 419; the sense strand comprises a nucleobase sequence of SEQ ID NO: 120, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 420; the sense strand comprises a nucleobase sequence of SEQ ID NO: 121, and the antisense strand comprises a nucleobase - 3 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsequence of SEQ ID NO: 421; the sense strand comprises a nucleobase sequence of SEQ ID NO: 122, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 422; the sense strand comprises a nucleobase sequence of SEQ ID NO: 123, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 423; the sense strand comprises a nucleobase sequence of SEQ ID NO: 124, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 424; the sense strand comprises a nucleobase sequence of SEQ ID NO: 125, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 425; the sense strand comprises a nucleobase sequence of SEQ ID NO: 126, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 426; the sense strand comprises a nucleobase sequence of SEQ ID NO: 127, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 427; the sense strand comprises a nucleobase sequence of SEQ ID NO: 128, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 428; the sense strand comprises a nucleobase sequence of SEQ ID NO: 129, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 429; the sense strand comprises a nucleobase sequence of SEQ ID NO: 130, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 430; the sense strand comprises a nucleobase sequence of SEQ ID NO: 131, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 431; the sense strand comprises a nucleobase sequence of SEQ ID NO: 132, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 432; the sense strand comprises a nucleobase sequence of SEQ ID NO: 133, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 433; the sense strand comprises a nucleobase sequence of SEQ ID NO: 134, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 434; the sense strand comprises a nucleobase sequence of SEQ ID NO: 135, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 435; the sense strand comprises a nucleobase sequence of SEQ ID NO: 136, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 436; the sense strand comprises a nucleobase sequence of SEQ ID NO: 137, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 437; the sense strand comprises a nucleobase sequence of SEQ ID NO: 138, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 438; the sense strand comprises a nucleobase sequence of SEQ ID NO: 139, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 439; the sense strand comprises a nucleobase sequence of SEQ ID NO: 140, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 440; the sense strand comprises a nucleobase sequence of SEQ ID NO: 141, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 441; the sense strand comprises a- 4 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTnucleobase sequence of SEQ ID NO: 142, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 442; the sense strand comprises a nucleobase sequence of SEQ ID NO: 143, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 443; the sense strand comprises a nucleobase sequence of SEQ ID NO: 144, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 444; the sense strand comprises a nucleobase sequence of SEQ ID NO: 145, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 445; the sense strand comprises a nucleobase sequence of SEQ ID NO: 146, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 446; the sense strand comprises a nucleobase sequence of SEQ ID NO: 147, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 447; the sense strand comprises a nucleobase sequence of SEQ ID NO: 148, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 448; the sense strand comprises a nucleobase sequence of SEQ ID NO: 149, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449; the sense strand comprises a nucleobase sequence of SEQ ID NO: 150, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450; the sense strand comprises a nucleobase sequence of SEQ ID NO: 151, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 451; the sense strand comprises a nucleobase sequence of SEQ ID NO: 152, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 452; the sense strand comprises a nucleobase sequence of SEQ ID NO: 153, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 453; the sense strand comprises a nucleobase sequence of SEQ ID NO: 154, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 454; the sense strand comprises a nucleobase sequence of SEQ ID NO: 155, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 455; the sense strand comprises a nucleobase sequence of SEQ ID NO: 156, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 456; the sense strand comprises a nucleobase sequence of SEQ ID NO: 157, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457; the sense strand comprises a nucleobase sequence of SEQ ID NO: 158, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 458; the sense strand comprises a nucleobase sequence of SEQ ID NO: 159, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 459; the sense strand comprises a nucleobase sequence of SEQ ID NO: 160, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 460; the sense strand comprises a nucleobase sequence of SEQ ID NO: 161, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 461; the sense strand comprises a nucleobase sequence of SEQ ID NO: 162, and the antisense strand - 5 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTcomprises a nucleobase sequence of SEQ ID NO: 462; the sense strand comprises a nucleobase sequence of SEQ ID NO: 163, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 463; the sense strand comprises a nucleobase sequence of SEQ ID NO: 164, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 464; the sense strand comprises a nucleobase sequence of SEQ ID NO: 165, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 465; the sense strand comprises a nucleobase sequence of SEQ ID NO: 166, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 466; the sense strand comprises a nucleobase sequence of SEQ ID NO: 167, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 467; the sense strand comprises a nucleobase sequence of SEQ ID NO: 168, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 468; the sense strand comprises a nucleobase sequence of SEQ ID NO: 169, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 469; the sense strand comprises a nucleobase sequence of SEQ ID NO: 170, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 470; the sense strand comprises a nucleobase sequence of SEQ ID NO: 171, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 471; the sense strand comprises a nucleobase sequence of SEQ ID NO: 172, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 472; the sense strand comprises a nucleobase sequence of SEQ ID NO: 173, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 473; the sense strand comprises a nucleobase sequence of SEQ ID NO: 174, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 474; the sense strand comprises a nucleobase sequence of SEQ ID NO: 175, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 475; the sense strand comprises a nucleobase sequence of SEQ ID NO: 176, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 476; the sense strand comprises a nucleobase sequence of SEQ ID NO: 177, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 477; the sense strand comprises a nucleobase sequence of SEQ ID NO: 178, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 478; the sense strand comprises a nucleobase sequence of SEQ ID NO: 179, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 479; the sense strand comprises a nucleobase sequence of SEQ ID NO: 180, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 480; the sense strand comprises a nucleobase sequence of SEQ ID NO: 181, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 481; the sense strand comprises a nucleobase sequence of SEQ ID NO: 182, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 482; the - 6 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsense strand comprises a nucleobase sequence of SEQ ID NO: 183, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 483; the sense strand comprises a nucleobase sequence of SEQ ID NO: 184, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 484; the sense strand comprises a nucleobase sequence of SEQ ID NO: 185, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 485; the sense strand comprises a nucleobase sequence of SEQ ID NO: 186, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 486; the sense strand comprises a nucleobase sequence of SEQ ID NO: 187, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 487; the sense strand comprises a nucleobase sequence of SEQ ID NO: 188, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 488; the sense strand comprises a nucleobase sequence of SEQ ID NO: 189, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 489; the sense strand comprises a nucleobase sequence of SEQ ID NO: 190, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 490; the sense strand comprises a nucleobase sequence of SEQ ID NO: 191, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 491; the sense strand comprises a nucleobase sequence of SEQ ID NO: 192, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 492; the sense strand comprises a nucleobase sequence of SEQ ID NO: 193, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 493; the sense strand comprises a nucleobase sequence of SEQ ID NO: 194, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 494; the sense strand comprises a nucleobase sequence of SEQ ID NO: 195, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 495; the sense strand comprises a nucleobase sequence of SEQ ID NO: 196, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 496; the sense strand comprises a nucleobase sequence of SEQ ID NO: 197, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 497; the sense strand comprises a nucleobase sequence of SEQ ID NO: 198, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 498; the sense strand comprises a nucleobase sequence of SEQ ID NO: 199, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 499; the sense strand comprises a nucleobase sequence of SEQ ID NO: 200, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 500; the sense strand comprises a nucleobase sequence of SEQ ID NO: 201, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 501; the sense strand comprises a nucleobase sequence of SEQ ID NO: 202, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 502; the sense strand comprises a nucleobase sequence of SEQ ID - 7 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTNO: 203, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 503; the sense strand comprises a nucleobase sequence of SEQ ID NO: 204, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 504; the sense strand comprises a nucleobase sequence of SEQ ID NO: 205, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 505; the sense strand comprises a nucleobase sequence of SEQ ID NO: 206, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 506; the sense strand comprises a nucleobase sequence of SEQ ID NO: 207, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 507; the sense strand comprises a nucleobase sequence of SEQ ID NO: 208, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 508; the sense strand comprises a nucleobase sequence of SEQ ID NO: 209, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 509; the sense strand comprises a nucleobase sequence of SEQ ID NO: 210, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 510; the sense strand comprises a nucleobase sequence of SEQ ID NO: 211, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 511; the sense strand comprises a nucleobase sequence of SEQ ID NO: 212, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 512; the sense strand comprises a nucleobase sequence of SEQ ID NO: 213, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 513; the sense strand comprises a nucleobase sequence of SEQ ID NO: 214, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 514; the sense strand comprises a nucleobase sequence of SEQ ID NO: 215, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 515; the sense strand comprises a nucleobase sequence of SEQ ID NO: 216, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 516; the sense strand comprises a nucleobase sequence of SEQ ID NO: 217, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 517; the sense strand comprises a nucleobase sequence of SEQ ID NO: 218, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 518; the sense strand comprises a nucleobase sequence of SEQ ID NO: 219, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 519; the sense strand comprises a nucleobase sequence of SEQ ID NO: 220, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 520; the sense strand comprises a nucleobase sequence of SEQ ID NO: 221, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 521; the sense strand comprises a nucleobase sequence of SEQ ID NO: 222, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 522; the sense strand comprises a nucleobase sequence of SEQ ID NO: 223, and the antisense strand comprises a nucleobase - 8 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsequence of SEQ ID NO: 523; the sense strand comprises a nucleobase sequence of SEQ ID NO: 224, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 524; the sense strand comprises a nucleobase sequence of SEQ ID NO: 225, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 525; the sense strand comprises a nucleobase sequence of SEQ ID NO: 1917, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1919; or the sense strand comprises a nucleobase sequence of SEQ ID NO: 1918, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1920.

[0010] In some embodiments, provided herein is a composition comprising a FN3 polypeptide domain linked to an siRNA molecule comprising a sense strand and an antisense strand that targets IFIH1 gene, wherein the FN3 polypeptide domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 1205, and wherein the siRNA molecule comprises: the sense strand comprises a nucleobase sequence of SEQ ID NO: 116, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 416; the sense strand comprises a nucleobase sequence of SEQ ID NO: 100, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 400; the sense strand comprises a nucleobase sequence of SEQ ID NO: 101, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 401; the sense strand comprises a nucleobase sequence of SEQ ID NO: 102, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 402; the sense strand comprises a nucleobase sequence of SEQ ID NO: 103, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 403; the sense strand comprises a nucleobase sequence of SEQ ID NO: 104, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 404; the sense strand comprises a nucleobase sequence of SEQ ID NO: 105, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 405; the sense strand comprises a nucleobase sequence of SEQ ID NO: 106, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 406; the sense strand comprises a nucleobase sequence of SEQ ID NO: 107, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 407; the sense strand comprises a nucleobase sequence of SEQ ID NO: 108, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 408; the sense strand comprises a nucleobase sequence of SEQ ID NO: 109, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 409; the sense strand comprises a nucleobase sequence of SEQ ID NO: 110, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 410; the sense strand comprises a nucleobase sequence of SEQ ID NO: 111, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 411; the - 9 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsense strand comprises a nucleobase sequence of SEQ ID NO: 112, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 412; the sense strand comprises a nucleobase sequence of SEQ ID NO: 113, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 413; the sense strand comprises a nucleobase sequence of SEQ ID NO: 114, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 414; the sense strand comprises a nucleobase sequence of SEQ ID NO: 115, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 415; the sense strand comprises a nucleobase sequence of SEQ ID NO: 117, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 417; the sense strand comprises a nucleobase sequence of SEQ ID NO: 118, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 418; the sense strand comprises a nucleobase sequence of SEQ ID NO: 119, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 419; the sense strand comprises a nucleobase sequence of SEQ ID NO: 120, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 420; the sense strand comprises a nucleobase sequence of SEQ ID NO: 121, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 421; the sense strand comprises a nucleobase sequence of SEQ ID NO: 122, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 422; the sense strand comprises a nucleobase sequence of SEQ ID NO: 123, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 423; the sense strand comprises a nucleobase sequence of SEQ ID NO: 124, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 424; the sense strand comprises a nucleobase sequence of SEQ ID NO: 125, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 425; the sense strand comprises a nucleobase sequence of SEQ ID NO: 126, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 426; the sense strand comprises a nucleobase sequence of SEQ ID NO: 127, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 427; the sense strand comprises a nucleobase sequence of SEQ ID NO: 128, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 428; the sense strand comprises a nucleobase sequence of SEQ ID NO: 129, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 429; the sense strand comprises a nucleobase sequence of SEQ ID NO: 130, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 430; the sense strand comprises a nucleobase sequence of SEQ ID NO: 131, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 431; the sense strand comprises a nucleobase sequence of SEQ ID NO: 132, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 432; the sense strand comprises a nucleobase sequence of SEQ ID - 10 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTNO: 133, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 433; the sense strand comprises a nucleobase sequence of SEQ ID NO: 134, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 434; the sense strand comprises a nucleobase sequence of SEQ ID NO: 135, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 435; the sense strand comprises a nucleobase sequence of SEQ ID NO: 136, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 436; the sense strand comprises a nucleobase sequence of SEQ ID NO: 137, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 437; the sense strand comprises a nucleobase sequence of SEQ ID NO: 138, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 438; the sense strand comprises a nucleobase sequence of SEQ ID NO: 139, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 439; the sense strand comprises a nucleobase sequence of SEQ ID NO: 140, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 440; the sense strand comprises a nucleobase sequence of SEQ ID NO: 141, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 441; the sense strand comprises a nucleobase sequence of SEQ ID NO: 142, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 442; the sense strand comprises a nucleobase sequence of SEQ ID NO: 143, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 443; the sense strand comprises a nucleobase sequence of SEQ ID NO: 144, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 444; the sense strand comprises a nucleobase sequence of SEQ ID NO: 145, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 445; the sense strand comprises a nucleobase sequence of SEQ ID NO: 146, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 446; the sense strand comprises a nucleobase sequence of SEQ ID NO: 147, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 447; the sense strand comprises a nucleobase sequence of SEQ ID NO: 148, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 448; the sense strand comprises a nucleobase sequence of SEQ ID NO: 149, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449; the sense strand comprises a nucleobase sequence of SEQ ID NO: 150, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450; the sense strand comprises a nucleobase sequence of SEQ ID NO: 151, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 451; the sense strand comprises a nucleobase sequence of SEQ ID NO: 152, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 452; the sense strand comprises a nucleobase sequence of SEQ ID NO: 153, and the antisense strand comprises a nucleobase - 11 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsequence of SEQ ID NO: 453; the sense strand comprises a nucleobase sequence of SEQ ID NO: 154, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 454; the sense strand comprises a nucleobase sequence of SEQ ID NO: 155, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 455; the sense strand comprises a nucleobase sequence of SEQ ID NO: 156, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 456; the sense strand comprises a nucleobase sequence of SEQ ID NO: 157, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457; the sense strand comprises a nucleobase sequence of SEQ ID NO: 158, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 458; the sense strand comprises a nucleobase sequence of SEQ ID NO: 159, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 459; the sense strand comprises a nucleobase sequence of SEQ ID NO: 160, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 460; the sense strand comprises a nucleobase sequence of SEQ ID NO: 161, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 461; the sense strand comprises a nucleobase sequence of SEQ ID NO: 162, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 462; the sense strand comprises a nucleobase sequence of SEQ ID NO: 163, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 463; the sense strand comprises a nucleobase sequence of SEQ ID NO: 164, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 464; the sense strand comprises a nucleobase sequence of SEQ ID NO: 165, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 465; the sense strand comprises a nucleobase sequence of SEQ ID NO: 166, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 466; the sense strand comprises a nucleobase sequence of SEQ ID NO: 167, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 467; the sense strand comprises a nucleobase sequence of SEQ ID NO: 168, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 468; the sense strand comprises a nucleobase sequence of SEQ ID NO: 169, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 469; the sense strand comprises a nucleobase sequence of SEQ ID NO: 170, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 470; the sense strand comprises a nucleobase sequence of SEQ ID NO: 171, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 471; the sense strand comprises a nucleobase sequence of SEQ ID NO: 172, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 472; the sense strand comprises a nucleobase sequence of SEQ ID NO: 173, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 473; the sense strand comprises a- 12 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTnucleobase sequence of SEQ ID NO: 174, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 474; the sense strand comprises a nucleobase sequence of SEQ ID NO: 175, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 475; the sense strand comprises a nucleobase sequence of SEQ ID NO: 176, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 476; the sense strand comprises a nucleobase sequence of SEQ ID NO: 177, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 477; the sense strand comprises a nucleobase sequence of SEQ ID NO: 178, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 478; the sense strand comprises a nucleobase sequence of SEQ ID NO: 179, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 479; the sense strand comprises a nucleobase sequence of SEQ ID NO: 180, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 480; the sense strand comprises a nucleobase sequence of SEQ ID NO: 181, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 481; the sense strand comprises a nucleobase sequence of SEQ ID NO: 182, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 482; the sense strand comprises a nucleobase sequence of SEQ ID NO: 183, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 483; the sense strand comprises a nucleobase sequence of SEQ ID NO: 184, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 484; the sense strand comprises a nucleobase sequence of SEQ ID NO: 185, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 485; the sense strand comprises a nucleobase sequence of SEQ ID NO: 186, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 486; the sense strand comprises a nucleobase sequence of SEQ ID NO: 187, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 487; the sense strand comprises a nucleobase sequence of SEQ ID NO: 188, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 488; the sense strand comprises a nucleobase sequence of SEQ ID NO: 189, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 489; the sense strand comprises a nucleobase sequence of SEQ ID NO: 190, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 490; the sense strand comprises a nucleobase sequence of SEQ ID NO: 191, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 491; the sense strand comprises a nucleobase sequence of SEQ ID NO: 192, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 492; the sense strand comprises a nucleobase sequence of SEQ ID NO: 193, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 493; the sense strand comprises a nucleobase sequence of SEQ ID NO: 194, and the antisense strand - 13 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTcomprises a nucleobase sequence of SEQ ID NO: 494; the sense strand comprises a nucleobase sequence of SEQ ID NO: 195, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 495; the sense strand comprises a nucleobase sequence of SEQ ID NO: 196, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 496; the sense strand comprises a nucleobase sequence of SEQ ID NO: 197, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 497; the sense strand comprises a nucleobase sequence of SEQ ID NO: 198, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 498; the sense strand comprises a nucleobase sequence of SEQ ID NO: 199, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 499; the sense strand comprises a nucleobase sequence of SEQ ID NO: 200, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 500; the sense strand comprises a nucleobase sequence of SEQ ID NO: 201, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 501; the sense strand comprises a nucleobase sequence of SEQ ID NO: 202, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 502; the sense strand comprises a nucleobase sequence of SEQ ID NO: 203, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 503; the sense strand comprises a nucleobase sequence of SEQ ID NO: 204, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 504; the sense strand comprises a nucleobase sequence of SEQ ID NO: 205, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 505; the sense strand comprises a nucleobase sequence of SEQ ID NO: 206, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 506; the sense strand comprises a nucleobase sequence of SEQ ID NO: 207, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 507; the sense strand comprises a nucleobase sequence of SEQ ID NO: 208, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 508; the sense strand comprises a nucleobase sequence of SEQ ID NO: 209, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 509; the sense strand comprises a nucleobase sequence of SEQ ID NO: 210, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 510; the sense strand comprises a nucleobase sequence of SEQ ID NO: 211, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 511; the sense strand comprises a nucleobase sequence of SEQ ID NO: 212, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 512; the sense strand comprises a nucleobase sequence of SEQ ID NO: 213, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 513; the sense strand comprises a nucleobase sequence of SEQ ID NO: 214, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 514; the - 14 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsense strand comprises a nucleobase sequence of SEQ ID NO: 215, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 515; the sense strand comprises a nucleobase sequence of SEQ ID NO: 216, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 516; the sense strand comprises a nucleobase sequence of SEQ ID NO: 217, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 517; the sense strand comprises a nucleobase sequence of SEQ ID NO: 218, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 518; the sense strand comprises a nucleobase sequence of SEQ ID NO: 219, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 519; the sense strand comprises a nucleobase sequence of SEQ ID NO: 220, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 520; the sense strand comprises a nucleobase sequence of SEQ ID NO: 221, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 521; the sense strand comprises a nucleobase sequence of SEQ ID NO: 222, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 522; the sense strand comprises a nucleobase sequence of SEQ ID NO: 223, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 523; the sense strand comprises a nucleobase sequence of SEQ ID NO: 224, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 524; the sense strand comprises a nucleobase sequence of SEQ ID NO: 225, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 525; the sense strand comprises a nucleobase sequence of SEQ ID NO: 1917, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1919; or the sense strand comprises a nucleobase sequence of SEQ ID NO: 1918, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1920, and wherein each nucleotide of the sense strand or the antisense strand is or is not a modified nucleotide.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a funnel chart representing the properties assessed and considered for siRNA screening.

[0012] FIG. 2 is a bar graph depicting selective downregulation of in vitro mRNA expression of IFIH1 as compared to other genes following administration of an exemplary IFIH1 -targeting siRNA. Differential expression signal is expressed as log2 fold change, with statistical significance calculated against a logarithmic fold change threshold of 0.585 (*** indicates a p value of < 0.0005, N. S. indicates no significant difference).- 15 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0013] FIG. 3 is a graph depicting decreasing expression of IF1H1 mRNA in VMRC cells transfected with IFIH1 -targeting siRNA, relative to IFIH1 mRNA expression in untreated control cells, as siRNA concentration (pM) increases.

[0014] FIG. 4 is a graph depicting decreasing expression of IFIH1 mRNA in Cal27 cells transfected with IFIH1 -targeting siRNA, relative to IFIH1 mRNA expression in untreated control cells, as siRNA concentration (pM) increases.

[0015] FIG. 5 is a graph depicting decreasing expression of IFIH1 mRNA in activated human dendritic cells in vitro treated with CD71 FN3-IFIH1 siRNA conjugates as the conjugate concentration (nM) increases. Relative IFIH1 mRNA expression is normalized to expression in untreated, activated control cells.

[0016] FIG. 6 is a series of three bar graphs depicting decreased production of Type 1 interferons IFN-a, IFN-0, and IFN- in donated human dendritic cells activated and exposed to high molecular weight polyinosinic-polycytidylic acid (poly(EC) HMW) in vitro, as compared to untreated dendritic cells activated and exposed to poly(EC) HMW (“positive control’’) and as compared to untreated, unexposed, activated dendritic cells (“negative control”).

[0017] FIG. 7A is a graph depicting decreasing expression of IFIH1 mRNA in activated human dendritic cells in vitro treated with CD71 FN3-ZFZH7 siRNA conjugates as the conjugate concentration (nM) increases. FIG. 7B is a graph depicting decreasing expression of IFIH1 mRNA in activated human dendritic cells in vitro treated with CD71 FN3-IFIH1 siRNA conjugates as the conjugate concentration (nM) increases. The cells from FIG. 7A are from a different donor than the cells from FIG. 7B. Relative IFIH1 mRNA expression is normalized to expression in untreated, activated control cells.

[0018] FIG. 8 is a set of two images visualizing the results of a Western blot analysis of expression of MDA5 protein and a housekeeping protein GAPDH in activated human dendritic cells in vitro four and seven days after treatment with CD71 FN3-IFIH1 siRNA conjugates.

[0019] FIG. 9A is a bar graph depicting IF1H1 reduction in stimulated dendritic cells.

[0020] FIG. 9B is a bar graph depicting IFNa reduction in stimulated dendritic cells.

[0021] FIG. 9C is a bar graph depicting IFNP reduction in stimulated dendritic cells.

[0022] FIG. 10A is a bar graph depicting IFIH1 reduction in stimulated Ml / proinflammatory macrophages.

[0023] FIG. 10B is a bar graph depicting IFNa reduction in stimulated Ml / proinflammatory macrophages.- 16 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0024] FIG. 10C is a bar graph depicting IFNP reduction in stimulated Ml / proinflammatory macrophages.

[0025] FIG. 11 A is a bar graph depicting Ifihl reduction in F4 / 80+ splenic macrophages.

[0026] FIG. 1 IB is a bar graph depicting IFNa reduction in serum.

[0027] FIG. 11C is a bar graph depicting IFNP reduction in serum.

[0028] FIG. 12 is a graph depicting median change in blood glucose concentration from week 5.

[0029] FIG. 13A is a bar graph depicting median change in blood glucose concentration from week 5.

[0030] FIG. 13B is a bar graph depicting change in absolute blood glucose concentration.

[0031] FIG. 14 is a graph depicting diabetes onset.

[0032] FIG. 15A is a bar graph depicting diabetes incidence.

[0033] FIG. 15B is a bar graph depicting diabetes mortality

[0034] FIG. 16 is a graph depicting relative IFIH1 mRNA expression.DETAILED DESCRIPTIONDefinitions

[0035] As used in this specification and the appended claims, the singular forms “a,” “an," and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0036] “Fibronectin type III (FN3) domain” (FN3 domain) refers to a polypeptide sequence that is an evolutionarily conserved protein domain occurring frequently in proteins including, but not limited to, fibronectins, tenascin, intracellular cytoskeletal proteins, cytokine receptors and prokaryotic enzymes (Bork and Doolittle, Proc Nat Acad Sci USA 89:8990-8994, 1992; Meinke et al., J Bacteriol 175:1910-1918, 1993; Watanabe et al., J Biol Chem 265:15659-15665, 1990). Exemplary FN3 domains are the 15 different FN3 domains present in human tenascin C, the 15 different FN3 domains present in human fibronectin (FN), and non-natural synthetic FN3 domains as described for example in U. S. Pat. No. 8,278,419. Individual FN3 domains are referred to by domain number and protein name, e.g., the 3rdFN3 domain of tenascin (TN3), or the 10thFN3 domain of fibronectin (FN10). As used throughout, “centyrin” also refers to an FN3 domain. Further, FN3 domains as described herein are not antibodies as they do not have the structure of a variable heavy (VH) and / or light (VL) chain.- 17 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0037] As used herein, “autoimmune disease” refers to disease conditions and states wherein the immune response of an individual is directed against the individual’s own constituents, resulting in an undesirable and often debilitating condition. “Autoimmune disease” includes, but is not limited to, autoimmune conditions, syndromes, and the like. Exemplary autoimmune diseases include Addison’s disease, allergy, allergic rhinitis, ankylosing spondylitis, asthma, atherosclerosis, autoimmune diseases of the ear, autoimmune diseases of the eye, autoimmune atrophic gastritis, autoimmune hepatitis, autoimmune hemolytic anemia, autoimmune parotitis, autoimmune uveitis, celiac disease, primary biliary cirrhosis, benign lymphocytic angiitis, COPD, colitis, coronary heart disease, Crohn's disease, depression, Type 1 diabetes, Type 2 diabetes, epididymitis, glomerulonephritis, Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease (IBD), immune response to recombinant drug products, e.g., factor VII in hemophilia, juvenile idiopathic arthritis, systemic lupus erythematosus, lupus nephritis, male infertility, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, oncology, osteoarthritis, pain, primary myxedema, pemphigus, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, spondyloarthropathies, sympathetic ophthalmia, T-cell lymphoma, T-cell acute lymphoblastic leukemia, testicular angiocentric T-cell lymphoma, thyroiditis, transplant rejection, ulcerative colitis, autoimmune uveitis, and vasculitis. Autoimmune diseases can also include conditions in which one or more tissues is / are the primary target, and in some cases, the secondary target. Such conditions can include, but are not limited to, Addison’s disease (e.g., autoimmune Addison’s disease), acute liver failure, acute pancreatitis, acute respiratory distress syndrome (ARDS), adult-onset Still’s disease, Alzheimer’s disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, asthma, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrine syndrome, autoimmune thrombocytopenic purpura (ATP), axial spondyloarthropathy, Bechet’s disease, cachexia (e.g., inflammation-associated carcinogenesis and cancer cachexia), celiac disease, cerebral edema, cardiomyopathy, chronic atherosclerosis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic liver failure, chronic obstructive pulmonary disease (COPD), chronic pancreatitis, chronic rhinosinusitis, Churg-Strauss syndrome, Cogan syndrome, colitis-associated cancer, congestive heart failure,- 18 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTCrohn’s disease, Cystic fibrosis, cytokine release syndrome, Degos’ disease, dermatitis herpetiformis, dermatomyositis, dermatomyositis-juvenile, diabetic macrovasculopathy, diabetic retinopathy, discoid lupus, endometriosis, eosinophilic esophagitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), essential mixed cryoglobulinemia, fibromyalgia, fibromyalgia-fibromyositis, fibrosis, glomemlonephritides, gout and gouty arthritis, graft-versus-host disease (GVHD), granulomatosis with polyangiitis (Wegener’s granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hepatitis B, hepatitis C, hepatitis C-associated autoimmune diseases, hereditary angioedema, hidradenitis suppurativa, HIV (human immunodeficiency virus)-associated autoimmune diseases, Hidradenitis suppurativa, IgA nephropathy, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), inclusion body myositis, inflammatory bowel disease, inflammatory bowel diseases, inflammatory myopathies, inflammatory syndrome following IL-2 administration, insulin-dependent diabetes mellitus, interstitial cystitis, interstitial lung disease, ischemic heart disease, Jarisch-Herxheimer reaction, juvenile chronic arthritis (Still’s disease), juvenile idiopathic arthritis (JIA), juvenile rheumatoid arthritis (JRA), Kawasaki disease, lichen planus, lichen sclerosus, loosening of prostheses, lupus erythematosus (systemic), Macular degeneration, mastocytosis, Meniere’s disease, microscopic polyangiitis, migraine, mixed connective tissue disease, mixed cryoglobulinemia, multiple myeloma, multiple sclerosis, multisystem inflammatory syndrome (MISC), myasthenia gravis, myelodysplastic syndromes, myocardial infarction, neuroinflammatory disorders (such as multiple sclerosis and neurosarcoidosis), neuropathic pain, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), nonradiographic axial spondyloarthritis, ocular inflammatory diseases (such as uveitis), oral lichen planus, orchitis, osteoarthritis, osteoporosis, Paget’s disease of bone, panciaticular vulgaris, paraneoplastic syndromes, pemphigus, periodontal disease, peripheral neuropathy, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, post-streptococcal glomerulonephritis or IgA nephropathy, primary agammaglobulinemia, primary biliary cholangitis, primary sclerosing cholangitis, progressive renal failure, pseudogout, psoriasis (including plaque psoriasis), psoriatic arthritis, pyoderma gangrenosum, reactive arthritis, Reiter’s syndrome, relapsing polychondritis, respiratory syncytial virus (RSV) infection, rheumatic fever, rheumatic heart disease, rheumatoid arthritis, rosacea, sarcoidosis, SARS-COV-2-related inflammation, sciatica, scleroderma (progressive systemic sclerosis (PSS), also known as systemic sclerosis (SS)), sclerosing cholangitis, sepsis, Sjogren’s syndrome, spondyloarthropathies, stroke, steroid-dependent - 19 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTgiant cell arteritis, Takayasu arteritis, temporal arteritis / giant cell arteritis, thoracoabdominal aortic aneurysm repair (TAAA), thrombotic thrombocytopenic purpura (TTP), TNF receptor-associated periodic syndrome (TRAPS), type 1 diabetes, type 2 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis (e.g., systemic vasculitis, vasculitis of one or more organ systems), vitiligo, Waldenstrom macroglobulinemia, Whipple’s disease, Wilson’s disease, Yellow Fever vaccination, and Zollinger-Ellison syndrome.

[0038] As used herein, “substituting” or “substituted” or “mutating” or “mutated” refers to altering, deleting and / or inserting one or more amino acids or nucleotides in a polypeptide or polynucleotide sequence to generate a variant of that sequence.

[0039] As used herein, “variant” refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more nucleic acids or amino acids. A variant may include a truncation from a reference sequence.

[0040] The term “positive cell” in reference to a protein refers to a cell that expresses the protein.

[0041] As used herein, “specifically binds” or “specific binding” refers to the ability of an FN3 domain to bind to its target, such as CD71, at least 5-fold above a negative control in a standard solution ELISA assay, with a dissociation constant (KD) of about IxlO-6M or less, for example, about IxlO-7M or less, about IxlO-8M or less, about IxlO-9M or less, about IxlO10M or less, about IxlO11M or less, about IxlO12M or less, or about IxlO13M or less. Specific binding can also be demonstrated using a proteome array as described herein. In some embodiments, a negative control is an FN3 domain that does not bind CD71. In some embodiments, an FN3 domain that specifically binds CD71 may have cross-reactivity to other related antigens, for example, to the same predetermined antigen from other species (homologs), such as Macaca fascicularis (cynomolgus monkey) or Pan troglodytes (chimpanzee).

[0042] As used herein, “library” refers to a collection of variants. The library may be composed of polypeptide or polynucleotide variants.

[0043] As used herein, “stability” refers to the ability of a molecule to maintain a folded state under physiological conditions such that it retains at least one of its normal functional activities, for example, binding to a predetermined antigen such as CD71

[0044] As used herein, “CD71” refers to human CD71 protein according to the amino acid sequence of SEQ ID NOs: 3 or 4. SEQ ID NO: 3 sets forth the amino acid sequence of full- 20 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTlength human CD71 protein. SEQ ID NO: 4 sets forth the amino acid sequence of the extracellular domain of human CD71 protein.

[0045] As used herein, “Tencon” refers to the synthetic fibronectin type III (FN3) domain having the consensus sequence:LPAPKNLWSEVTEDSLRLSWTAPDAAFDSFLIQYQESEKVGEAINLTVPGSERSYDLTGLK PGTEYTVSIYGVKGGHRSNPLSAEFTT (SEQ ID NO: 1),and described in U. S. Pat. Pub. No. 2010 / 0216708.

[0046] As used herein, an “immune cell” refers to cells of the immune system of a subject categorized as lymphocytes (T cells, B cells and natural killer (NK) cells), neutrophils, or monocytes / macrophages. Immune cells also include dendritic cells. A “dendritic cell” refers to a type of antigen-presenting cell (APC) that forms an important role in the adaptive immune system. The main function of dendritic cells is to present antigens to T lymphocytes, and to secrete cytokines that may further modulate the immune response directly or indirectly. Dendritic cells have the capacity to induce a primary immune response in inactive or resting naive T lymphocytes.

[0047] As used herein, “vector” refers to a polynucleotide capable of being duplicated within a biological system or that can be moved between such systems. Vector polynucleotides typically contain elements, such as origins of replication, polyadenylation signal or selection markers that function to facilitate the duplication or maintenance of these polynucleotides in a biological system. Examples of such biological systems may include a cell, vims, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector. A vector may be comprised of a DNA or RNA molecule, or a hybrid of these.

[0048] As used herein, “expression vector” refers to a vector that can be utilized in a biological system or in a reconstituted biological system to direct the translation of a polypeptide encoded by a polynucleotide sequence present in the expression vector.

[0049] The term "nucleobase sequence" refers to the sequence of purine and pyrimidine bases (adenine, guanine, cytosine, thymine, and uracil, or analogues thereof) that encode the genetic information and determine the specificity of a nucleic acid molecule. The nucleobase sequence represents the fundamental informational content independent of any chemical modifications to the sugar-phosphate backbone or other structural components of the nucleic acid.

[0050] The term "nucleic acid sequence" refers to the complete chemical structure of an oligonucleotide or polynucleotide, including the nucleobase sequence as well as any chemical - 21 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmodifications to the sugar moieties, phosphate backbone, or nucleobases themselves. Such modifications may include, but are not limited to, 2'-O-methyl modifications, 2'-fluoro modifications, phosphorothioate linkages, locked nucleic acids (LNA), unlocked nucleic acids (UNA), peptide nucleic acids (PNA), morpholino modifications, and base modifications. Thus, a nucleic acid sequence comprises the nucleobase sequence and any additional chemical modifications that enhance stability, binding affinity, nuclease resistance, or other properties relevant to therapeutic or diagnostic applications.

[0051] As used herein, “polynucleotide” refers to a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. A complementary deoxyribonucleic acid (cDNA) is an example of a common polynucleotide. Example nucleotides described herein include adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U). One of skill in the art will appreciate that thymine (T) can generally be replaced with uracil (U) in sequences disclosed herein (e.g., in RNA sequences) and vice versa.

[0052] As used herein, “polypeptide” or “protein” refers to a molecule that comprises at least two amino acid residues linked by a peptide bond to form a polypeptide. Small polypeptides of less than about 50 amino acids may be referred to as “peptides”.

[0053] As used herein, “valent” refers to the presence of a specified number of binding sites specific for an antigen in a molecule. As such, the terms “monovalent”, “bivalent”, “tetravalent”, and “hexavalent” refer to the presence of one, two, four, and six binding sites, respectively, specific for an antigen in a molecule.

[0054] As used herein, “subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Except where noted, the terms “patient” or “subject” are used interchangeably.

[0055] As used herein, “isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or polypeptides such as FN3 domains) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated FN3 domain” refers to an FN3 domain that is substantially free of other cellular material and / or chemicals and encompasses FN3 domains that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%. 84%. 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.- 22 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0056] As used herein, “migration,” when used in reference to the movement of cells, means that the cells are moving from one location to another. For example, a cell (e.g., a white blood cell or an immune cell) moving from a blood vessel to a tissue can be said to be migrating from the blood vessel to the tissue. Migration can also include the process of “margination,” which refers to a cell moving from the interior of a blood vessel towards the blood vessel wall. Migration can also include adhesion of the cell to the blood vessel wall, as well as transmigration across the blood vessel wall to enter a tissue.

[0057] As used herein, “treat” or “treatment” or “treating” refer to impacting a disease, disorder, symptom, or manifestation of such in a subject by preventing, inhibiting, ameliorating, mitigating, or otherwise relieving one or more symptoms of the disease or disorder. As used herein “prevent” or “preventing” can mean resulting in causing a disease, disorder, symptom, or manifestation not to occur at all (e.g., prophylaxis), not to occur for a period of time, or not to worsen.The Immune System

[0058] The immune system is an extraordinarily complex collection of interrelated signaling pathways and cellular responses responsible for maintaining the integrity of a subject’s body, preventing and / or fighting disease, and responding to injury (e.g., trauma). Immunity is generally categorized as adaptive or innate. The adaptive immune system is generally specific for particular pathogens and able to provide long-lasting protection. The innate immune system tends to be less specific, defending the body against, e.g., foreign organisms. Though the adaptive immune system can destroy pathogens, it may also have difficulty distinguishing between pathogens and non-pathogens, resulting in so-called autoimmune conditions, such as allergies. The responses mediated by the adaptive immune system are further divided into humoral and cell-mediated responses, driven by B lymphocytes (associated with, e.g., production of immunoglobulins) and T lymphocytes (associated with, e.g., cell-mediated cytotoxicity), respectively.

[0059] Immune responses are largely mediated, in whole or in part, by cytokines, a well-studied category of small, secreted proteins that are large drivers of immune responses and effects. Cytokines play important roles in cell signaling and are primarily produced and released by T lymphocytes. T lymphocytes can include antigen-specific receptors on their surfaces that facilitate recognition of foreign pathogens in the body, and can distinguish between “self’ and “non-self ’ identities. T lymphocytes can be further classified by whether CD4 or CD8 molecules are expressed on their surfaces. Generally, T cells expressing CD8 - 23 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTare characterized as cytotoxic T cells, while those expressing CD4 are known as helper T (“Th”) cells.

[0060] Th cells are the largest producers of cytokines in the human body. Th cells differentiate from their progenitors into effector, memory, or regulatory Th cell phenotypes. Effector Th cells may be further classified into two major subtypes, helper type 1 T cells (Thl cells) or helper type 2 T cells (Th2 cells), based on the type of cytokines they secrete. Thl and Th2 cells induce immune responses that are reciprocally inhibitory, and immune homeostasis requires a balance between the two. Immune dysfunction (such as autoimmunity or anaphylaxis) may result when an immune system is easily or chronically biased towards one phenotype or another, either as a baseline state or in response to an event.The Immune System: Thl Responses

[0061] Thl cells are important for cell-mediated immunity and host defense from intracellular pathogens. These cells secrete pro-inflammatory cytokines which cause macrophages and other types of lymphocytes to phagocytose microbial pathogens. Thl -type, pro-inflammatory cytokines include, e.g., IFN-y, IL-2, TNF-, IL-12, and / or immunoglobulins such as IgG2. Such Thl -type cytokines are, inter alia, responsible for killing intracellular pathogens (e.g., parasites, which may include viruses and / or bacteria), and can also underlie autoimmunity. Uncontrolled or excessive Thl -mediated pro-inflammatory responses can result in significant tissue damage. A Thl immune response may include a variety of specific immune responses. A Thl immune response may be characterized by decreased activity of one or more of IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IgE, and histamines, relative to administration of a Th2-associated antigen to the subject. A Thl response may be characterized by increased activity of one or more of IFN-y, IL-2, TNF-P, IL-12, and IgG2a, relative to administration of a Th2-associated antigen to the subject.

[0062] Thl cells derive from the alpha:beta lineage of T cells and recognize antigens presented by major histocompatibility complex (MHC) class I or II molecules. These cells play a critical role in the identification and eradication of intracellular pathogens such as viruses and bacteria, which typically reside in phagocytic vesicles within cells such as macrophages, and often evade intracellular killing by preventing lysosomal fusion. Thl cells help to activate macrophages against these pathogens and overcome microbial evasion strategies. The main effector functions of Thl cells are in cell-mediated immunity and inflammation, including the activation of cytolytic and other effector functions of other- 24 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTimmune cells such as macrophages, B cells, and CD8+ cytotoxic T lymphocytes (see, e.g., Luckheeram et al. Clin Dev Immunol 2012:925135).

[0063] As used herein, “Thl mediated” refers to a response in which Thl cells are active and facilitating or driving a response (e.g., a cellular response, such as an immune response) and “activating” refers to the multi-step process comprising the steps of antigen uptake, processing, and cell surface expression bound to class II MHC molecules by an antigen presenting cell, recirculation, and antigen specific trapping of helper T cell precursors in lymphoid tissue, and T cell proliferation and differentiation. At the time of activation, the naive T cells are driven to differentiate into Thl cells by early exposure to IFN-y and IL-12.

[0064] As used herein, “Thl -associated antigen” refers to any antigen typically associated with Thl -mediated responses. A Thl -associated antigen causes a predominantly Thl-mediated immune response in a subject exposed to the antigen.The Immune System: Thl Responses

[0065] Th2 cells are important for humoral immunity. These cells secrete cytokines protecting against, e.g., extracellular parasites, and stimulating the production of antibodies. Th2-type cytokines include interleukins 4, 5, 10, and 13. Th2-type cytokines and Th2 immune responses are associated with atopy and allergy, as well as with the promotion of IgE-mediated and eosinophilic responses and general anti-inflammatory effects. In excess, Th2-type cytokines counteract Thl responses, which may be detrimental to the host organism.

[0066] A Th2 immune response may include a variety of specific immune responses. A Th2 immune response may be characterized by increased activity of one or more of IL-4, IL-5, IL-6, IL-9, IL- 10, IL-13, IgE, and histamines, relative to administration of a Thl -associated antigen to the subject. A Th2 response may be characterized by decreased activity of one or more of IFN-y, IL-2, TNF-0, IL-12, and IgG2a, relative to administration of a Thl -associated antigen to the subject. Those skilled in the art will appreciate that certain antigens are typically associated with Thl and / or Th2 responses. In some embodiments, an antigen may be or comprise a Th2-associated antigen for humans, for a particular subject, or for a group of subjects. In some embodiments, a Th2 immune response may be or comprise an increase in at least one Th2-associated cytokine (e.g., IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IgE, and histamines,). In some embodiments, a Th2 immune response may be or comprise a decrease in one or more Thl -associated cytokines (e.g., IFN-y, IL-2, TNF-0, IL-12, and IgG2a, among others).- 25 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0067] As used herein, T helper type 2 (Th2) cells are the other major subset of CD4+ T cells in congruence with Thl. In contrast to Thl cells, Th2 cells help to recognize extracellular pathogens and activate B cell-mediated antibody responses. Th2 cells can mediate activation and maintenance of humoral, or antibody-mediated, immune responses against extracellular insults by producing various cytokines responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions. As Th2 cells influence the production of antibodies and allergic responses, when overactivated they are thought to be responsible for the exacerbation of allergies and autoimmune reactions and the development of inflammatory diseases {see, e.g., Roche & Furuta, Nat Rev Immunol. 14(4):203-l 6).

[0068] As used herein, “Th2-associated antigen” refers to any antigen typically associated with Th2-mediated responses. A Th2-associated antigen causes a predominantly Th2-mediated immune response in a subject exposed to the antigen.

[0069] In some embodiments, an antigen may be or comprise a Thl -associated antigen, either in general for humans or in a particular subject, or group of subjects. In some embodiments, a Thl response may be or comprise an increase in at least one Thl -associated cytokine {e.g., IFN-y, IL-2, TNF-0, IL-12, and IgG2a). In some embodiments, a Thl immune response may be or comprise a decrease in one or more Th2-associated cytokines {e.g., IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IgE, and histamines).

[0070] Exemplary criteria for identifying and selecting effective Th2-associated antigenic peptides {e.g., minimal peptide sequences capable of activating a Th2 immune response in a subject) may be found in the art. For example, Apostolopoulos, et al. (Curr. Opin. Mol. Then, 2:29-36 (2000)), discusses a strategy for identifying minimal antigenic peptide sequences based on an understanding of the three-dimensional structure of an antigen-presenting molecule and its interaction with both an antigenic peptide and T-cell receptor. As another example, Shastri, (Curr. Opin. Immunol., 8:271-7 (1996)), discusses a strategy to distinguish rare peptides that serve to activate T cells from the thousands of peptides normally bound to MHC molecules.

[0071] Those of skill in the art will recognize a wide variety of potential applications utilizing combinations of Th2-associated antigens, each of which is contemplated as being within the scope of the present disclosure.

[0072] In some embodiments, the composition comprising a Th2-associated antigen or other Th2-associated protein may comprise the antigen or other protein in any of a variety of forms. Exemplary forms include, without limitation, RNA, DNA, polypeptides, proteins, and combinations thereof. In some embodiments, the antigen or protein may be provided in a - 26 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTcrude form, such as a portion of a cell, tissue or extract thereof. In some embodiments, the antigen or protein is not substantially pure.

[0073] In some embodiments, administration of provided compositions results in immune desensitization to the antigen. In some embodiments, the desensitization is characterized by a decreased Th2 immune response. In some embodiments, the desensitization is characterized by an increased Thl immune response.IFIH1 / MDA5 Axis in Disease

[0074] MDA5, which is encoded by IFIH1, is a cytosolic sensor specialized to detect long double-stranded RNA (dsRNA) and to initiate a potent antiviral-type I interferon (IFN-I) program when it oligomerizes on ligand. Single-molecule and structural / biochemical studies define MDA5 filament assembly as a length- and stability-dependent process in which long, rigid duplexes drive cooperative oligomerization and downstream MAVS-IRF signaling; small changes in ligand abundance, duplex length, or receptor sensitivity therefore produce large shifts in interferon output. See Sadeem Ahmad et al., Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation. 172 Cell 797, 799-804 (2018): and Peisley et al., Cooperative Assembly and Dynamic Disassembly of MDA5 Filaments for Viral dsRNA Recognition, 108 Proc. NatT Acad. Sci. U. S. A. 21010 (2011).

[0075] Because MDA5 lies at the interface of antiviral defense and autoinflammation, modest increases in receptor activity or exposure to immunogenic endogenous RNAs can convert protective sensing into pathologic, chronic IFN signaling. Human genetics and rare disease sequencing identify both gain-of-function IFIH1 alleles and IFIHl-linked Mendelian interferonopathies (for example, Singleton-Merten and Aicardi-Goutieres-type phenotypes) in which heightened MDA5 activity produces systemic IFN signatures and tissue damage. Conversely, IFIH1 loss-of-function alleles are associated with reduced risk in some common inflammatory diseases, indicating that tuning IFIH1 activity has disease-modifying potential. See Ahmad et al., supra, at 797-800; Qiong Li et al., RNA Editing Underlies Genetic Risk of Common Inflammatory Diseases, 608 Nature 569, 569-575 (2022); and Erez Y. Levanon et al., In Search of Critical dsRNA Targets ofADARl, 40 Trends Genet. 250, 257-258 (2024).

[0076] Functionally, multiple experimental systems show that the dominant downstream consequence of pathological MDA5 activation is a stereotyped interferon-stimulated gene (ISG) program that alters cell state and function. In primary human cell models, activation of MDA5 produces robust ISG induction together with transcriptional reprogramming (including NF-KB and stress pathways), cell-intrinsic phenotypic changes, and secretion of - 27 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTchemokines that recruit and shape local immune infiltrates. Importantly for therapeutic siRNA strategies, targeted knockdown of IFIH1 with siRNAs substantially abrogates these IFN and ISG responses in vitro: co-knockdown of IFIH1 reverses the large majority of the transcriptomic ISG program induced by upstream perturbations, demonstrating that directly lowering IFIH1 expression is sufficient to blunt pathological signaling at the sensor level. See Ahmad et al., supra, at 800-808; Li et al., supra, at 569-575.

[0077] Tissue-specific evidence links pathological MDA5 signaling to clinically important diseases and to multiple, non-immune cell types. In pancreatic islets, IFIH1 activity is functionally implicated in early stages of type 1 diabetes: experimental models show that elevating IFIH1 signaling (or otherwise exposing pancreatic P cells to immunostimulatory dsRNA) provokes an IFN-I transcriptional state, -cell stress and dysfunction, islet immune infiltration, and progression to diabetes, whereas Ifihl deficiency prevents spontaneous autoimmune diabetes in susceptible mouse strains, supporting a model in which cell-intrinsic MDA5 sensing in cells contributes to disease initiation and progression. See Udi Ehud Knebel et al., Disrupted RNA Editing in Beta Cells Mimics Early-Stage Type 1 Diabetes. 36 Cell Metabolism 48, 48-61 (2024); Li et al., supra, at 569-575.

[0078] In the vasculature, vascular smooth muscle cells (SMCs) and other plaque-resident cells show pathological MDA5 / IFIH1 signaling that correlates with inflammation, phenotypic switching, plaque instability and calcification. Human plaque transcriptomics and conditional genetic models demonstrate that heightened MDA5 activity in SMCs drives an ISG program, alters lineage markers and transcription factors linked to disease, and accelerates atherogenesis; importantly, suppression of IFIH1 / MDA5 in these settings reduces the inflammatory phenotype and restores elements of normal SMC identity, supporting a causative role for the sensor in coronary artery disease pathology. See Li et al., supra, at 569-575; Levanon et al., supra, at 257-259.

[0079] Beyond islets and vessel wall, a broad set of parenchymal and stromal cell types express IFIH1 and are capable of mounting cell-intrinsic MDA5 responses under stress or in disease contexts. Single-cell and bulk transcriptomic surveys identify enrichment of IFN signatures and IFIH1 expression in endothelial cells, fibroblasts, epithelial compartments, progenitors and select neuronal cell types in inflamed tissues; in each case, cell-autonomous IFIH1 activation remodels local tissue biology (for example by driving chemokine release, extracellular matrix remodeling, matrix-metalloproteinase induction, or phenotypic transitions) and thereby amplifies tissue inflammation. These findings indicate that MDA5-driven pathology is not restricted to canonical immune effectors but extends to multiple - 28 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTCD71 -expressing parenchymal cells implicated across metabolic, cardiovascular and organspecific autoimmune diseases. See Levanon et al., supra, at 250-259; Li et al., supra, at 569-575.

[0080] Practically, the use of siRNA to downregulate IFIH1 provides a direct, mechanistically justified means to interrupt the MDA5 axis at its source. The same experimental datasets that map MDA5 dependence of pathological transcriptional programs also show that IFIH1 siRNA co-treatment normalizes gene expression, prevents ISG upregulation and blocks downstream phenotypic consequences in primary human cells and in vitro models relevant to disease (for example, human coronary artery SMCs and human islet cells). These data demonstrate both target-engagement feasibility and functional rescue by IFIH1 knockdown, supporting siRNA-based therapeutic approaches that selectively reduce MDA5 signaling in disease-relevant cell populations. See Ahmad et al., supra, at 807-808; Li et al., supra, at 573-575.

[0081] Taken together, the IFIH1 / MDA5 axis constitutes a nodal, druggable driver of pathologic interferon biology across multiple cell types and disease states. Where elevated MDA5 activity (by genetic variation, environmental trigger, metabolic or replicative stress, or altered RNA architecture) produces maladaptive IFN responses that damage tissue, selective reduction of IFIH1 expression, for example via targeted siRNA delivery to CD71 -expressing parenchymal or immune cells, offers a rational strategy to extinguish the upstream sensor stimulus, lower ISG burden, and break feed-forward inflammatory circuits that drive diseases such as type 1 diabetes, coronary artery disease, and interferonopathy syndromes.

[0082] Accordingly, as used herein, the term “IFIH1 / MDA5 axis” refers to the molecular, cellular, and signaling pathway(s) involving interferon induced with helicase C domain 1 (IFIH1), also known as melanoma differentiation-associated protein 5 (MDA5), including IFIH1 gene expression, MDA5 protein expression, activation, oligomerization, ligand recognition, downstream signal transduction, and resulting biological effects. The IFIH1 / MDA5 axis includes sensing of double-stranded RNA or RNA structures by MDA5; activation of downstream adaptor proteins (including MAVS); induction of type I and / or type III interferon signaling; expression of interferon-stimulated genes; production of cytokines and chemokines; and consequent modulation of innate and adaptive immune responses, cellular stress responses, inflammatory pathways, and disease-associated phenotypes.

[0083] The IFIH1 / MDA5 axis may be activated or modulated by endogenous or exogenous RNA species, genetic variation in IFIH1, cellular stress, infection, metabolic or proliferative states, or other environmental or pathological stimuli. Dysregulation of the IFIH1 / MDA5 axis - 29 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTincludes, without limitation, increased or inappropriate IFIH1 expression or activity, heightened basal or ligand-induced signaling, prolonged interferon or inflammatory responses, or failure to appropriately resolve signaling, and is associated with autoimmune, autoinflammatory, metabolic, cardiovascular, neuroinflammatory, infectious, and other disease states. Modulation of the IFIH1 / MDA5 axis includes, without limitation, reduction, inhibition, attenuation, normalization, or regulation of any component or output of the axis, including IFIH1 gene expression or MDA5 protein activity.Compositions

[0084] In some embodiments, the present disclosure provides compositions binding at least one antigen. In some embodiments, the antigen is or comprises an allergic antigen, an anaphylactic antigen, an infectious antigen, an autoantigen, or a disease-associated antigen. In some embodiments, the antigen is or comprises an allergic antigen. In some embodiments, the antigen is or comprises an anaphylactic antigen. In some embodiments, the antigen is or comprises an infectious antigen. In some embodiments, the antigen is or comprises an autoantigen. In some embodiments, the antigen is or comprises a disease-associated antigen, such as a Thl -associated antigen or a Th2-associated antigen. In some embodiments, the antigen is a Thl -associated antigen. In some embodiments, the antigen is a Th2-associated antigen.

[0085] In some embodiments, the binding of the composition to at least one antigen results in an immune response in a subject. In some embodiments, the immune response is or comprises a predominantly Thl -mediated response. In some embodiments, the immune response is or comprises a predominantly Th2-mediated response. In some embodiments, the immune response is or comprises a Treg-mediated response. In some embodiments, the immune response is or comprises a Thl7-mediated response.

[0086] In some embodiments, the at least one antigen is a Th2-associated antigen and the immune response is not a predominantly Th2 -mediated response. In some embodiments, the antigen is a Thl -associated antigen and the immune response is not a predominantly Thl-mediated response.

[0087] Further provided herein are compositions and pharmaceutical compositions comprising a means for reducing expression of an IF1H1 gene in a cell. In some embodiments, the cell is a CD71 positive cell. In some embodiments, the cell is an immune cell.- 30 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0088] In some embodiments, the compositions described herein target, bind to, and are internalized by any cell that expresses CD71 (transferrin receptor 1) at any level sufficient to permit binding and uptake. CD71 is broadly expressed across a wide range of cell types, tissues, developmental stages, and physiological or pathological states.

[0089] In some embodiments, the CD71 -positive cell is an immune cell. Immune cells that may be targeted include, but are not limited to, T lymphocytes (including CD4 T cells, CD8+T cells, naive T cells, effector T cells, memory T cells, regulatory T cells, Thl cells, Th2 cells, Thl7 cells, T follicular helper cells, and cytotoxic T lymphocytes), B lymphocytes (including naive B cells, memory B cells, plasma cells, plasmablasts, and antibody-secreting cells), natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells (including conventional dendritic cells, plasmacytoid dendritic cells, and monocyte-derived dendritic cells), monocytes, macrophages (including Ml and M2 macrophages, tissue-resident macrophages, and inflammatory macrophages), neutrophils, eosinophils, basophils, mast cells, myeloid-derived suppressor cells, and combinations thereof.

[0090] In some embodiments, the CD71 -positive cell is a hematopoietic or progenitor cell. Such cells include, but are not limited to, hematopoietic stem cells, multipotent progenitor cells, common myeloid progenitors, common lymphoid progenitors, erythroid progenitors, megakaryocyte progenitors, myeloid progenitors, lymphoid progenitors, and other dividing or metabolically active precursor cell populations expressing CD71.

[0091] In some embodiments, the CD71 -positive cell is a pancreatic or endocrine cell. Such cells include, but are not limited to, pancreatic P cells, a cells, 3 cells, PP cells, s cells, pancreatic progenitor cells, endocrine progenitor cells, islet cells, and endocrine cells of the adrenal gland, thyroid, parathyroid, pituitary, hypothalamus, and gonads.

[0092] In some embodiments, the CD71 -positive cell is a cardiovascular or vascular cell. Such cells include, but are not limited to, vascular smooth muscle cells, endothelial cells, pericytes, fibroblasts, adventitial cells, myofibroblasts, cardiomyocytes, cardiac fibroblasts, cardiac progenitor cells, endothelial progenitor cells, vascular progenitor cells, and cells within the arterial, venous, capillary, and lymphatic vasculature.

[0093] In some embodiments, the CD71 -positive cell is an epithelial cell. Epithelial cells that may be targeted include, but are not limited to, epithelial cells of the gastrointestinal tract, respiratory tract, genitourinary tract, hepatobiliary system, pancreas, skin, and ocular surface, including enterocytes, goblet cells, Paneth cells, hepatocytes, cholangiocytes, renal tubular epithelial cells, podocytes, keratinocytes, basal epithelial cells, secretory epithelial cells, and epithelial progenitor cells.- 31 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0094] In some embodiments, the CD71 -positive cell is a stromal or mesenchymal cell. Such cells include, but are not limited to, fibroblasts, myofibroblasts, mesenchymal stem cells, stromal cells, adipocytes, preadipocytes, chondrocytes, osteoblasts, osteoclasts, osteocytes, synoviocytes, tenocytes, ligament cells, and connective tissue progenitor cells.

[0095] In some embodiments, the CD71 -positive cell is a nervous system cell. Such cells include, but are not limited to, neurons, neuronal progenitor cells, neural stem cells, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, microglia, Schwann cells, satellite glial cells, peripheral nervous system cells, and central nervous system support cells.

[0096] Unless expressly limited, all embodiments described herein that reference CD71-positive cells are intended to encompass any cell type, tissue, organ system, or disease context in which CD71 is expressed, either constitutively or inducibly. Expression of CD71 may be transient, developmentally regulated, disease-associated, stress-induced, or therapeutically induced, and all such CD71 -positive states are expressly contemplated. The compositions and methods described herein are therefore applicable to IFIH1 modulation in any CD71 -positive cell without limitation.

[0097] In some embodiments, the compositions described herein are suitable for administration to a subject regardless of IFIH1 genotype. In some embodiments, the subject has a wild-type IFIH1 allele. In some embodiments, the subject has one or more IFIH1 risk variant alleles. In some embodiments, the IFIH1 risk variant comprises the rsl990760 single nucleotide polymorphism encoding the A946T amino acid substitution. In some embodiments, the subject is heterozygous or homozygous for the IFIH1 A946T variant.

[0098] In some embodiments, the subject carrying the IFIH1 A946T variant exhibits increased basal interferon signaling and / or enhanced interferon production in response to double-stranded RNA stimulation as compared to a subject carrying the wild-type IFIH1 allele. In some embodiments, increased basal expression of interferon- and interferon-stimulated genes is observed in cells from subjects carrying the IFIH1 A946T variant. In such embodiments, inhibition or reduction of IFIH1 / MDA5 activity using the compositions described herein is expected to reduce excessive interferon signaling and provide therapeutic benefit.

[0099] In some embodiments, the subject with wild-type IFIH1 alleles may also benefit from administration of the disclosed compositions. In some embodiments, wild-type IFIH1 contributes to autoimmune, autoinflammatory, or inflammatory disease in the presence of environmental triggers, cellular stress, or additional genetic risk factors. Accordingly, in some embodiments, the compositions described herein may be administered to a subject with - 32 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTeither wild-type or variant IFIH1 alleles when dysregulated interferon signaling contributes to disease pathology.

[0100] In some embodiments, the means for reducing expression of an IF1H1 gene in a cell comprises an oligonucleotide. In some embodiments, the oligonucleotide is an siRNA molecule. In some embodiments, the means for reducing expression of an IFIH1 gene in a cell occurs by sequence specific interaction with an IFIH1 mRNA molecule. In some embodiments, the IFIH1 mRNA molecule comprises the nucleic acid sequence of SEQ ID NO: 46, as described herein.

[0101] In some embodiments, the composition comprises a means for reducing expression of an IFIH1 gene in a cell, wherein the means for reducing expression of the IFIH1 gene in the cell comprises an siRNA molecule. In some embodiments, the composition comprises a means for reducing expression of an IFIH1 gene in a cell, wherein the means for reducing expression of the FFIH1 gene in the cell occurs by sequence specific interaction with an IFIH1 mRNA molecule comprising the nucleic acid sequence of SEQ ID NO: 46, as described herein.

[0102] Further provided herein are compositions comprising a polypeptide, such as a polypeptide linked to an oligonucleotide molecule. In some embodiments, the polypeptide can be, for example, an FN3 domain. In some embodiments, the oligonucleotide molecule can be, for example, an siRNA molecule. In some embodiments, the FN3 domain is a CD71 binding FN3 domain as provided for herein. In some embodiments, the siRNA molecule is an siRNA molecule that binds to an 1F1FH RNA, such as mRNA as provided for herein. In some embodiments, the composition further comprises a polymer as provided for herein.

[0103] In some embodiments, the siRNA molecule is a double-stranded RNAi (dsRNA) agent capable of inhibiting the expression of a target gene. The dsRNA agent comprises a sense strand (passenger strand) and an antisense strand (guide strand). In some embodiments, each strand of the dsRNA agent can range from 12-40 nucleotides in length. For example, each strand can be from 14-40 nucleotides in length, 17-37 nucleotides in length, 25-37 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, about 16-25 nucleotides in length, 1 -25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length. In some embodiments, the sense strand consists essentially of 19 or 20 nucleotides. In some embodiments the antisense strand consists essentially of 21 nucleotides. In some embodiments, the siRNA molecule comprises a sense strand and an antisense strand, wherein the antisense strand targets IFIH1.- 33 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0104] In some embodiments, the sense strand and antisense strand typically form a duplex dsRNA. The duplex region of a dsRNA agent may be from 12-40 nucleotide pairs in length. For example, the duplex region can be from 14-40 nucleotide pairs in length, 17-30 nucleotide pairs in length, 25-35 nucleotides in length, 27-35 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length. In another example, the duplex region is selected from 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotide pairs in length. In some embodiments, the siRNA molecule does not contain any modified nucleobases. In some embodiments, the siRNA molecule further comprises a linker covalently attached to one or both of the sense strand or the antisense strand. In some embodiments, the linker is covalently attached to the sense strand. In some embodiments, the linker is covalently attached to the antisense strand. In some embodiments, the linker is covalently attached to both the sense strand and the antisense strand.

[0105] In some embodiments, the dsRNA comprises one or more overhang regions and / or capping groups of dsRNA agent at the 3’ end, or 5’ end, or both ends of a strand. The overhang can be 1-10 nucleotides in length, 1-6 nucleotides in length, for instance 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the target mRNA, or it can be complementary to the gene sequences being targeted, or it can be another sequence. The first and second strands can also be joined, e.g., by additional bases to form a hairpin, or by other non -base linkers.

[0106] In some embodiments, the nucleotides in the overhang region of the dsRNA agent can each independently be a modified or unmodified nucleotide including, but not limited to, 2’ -sugar modified, such as 2’-F, 2'-O-methyl, 2’-O-(2-methoxyethyl), 2’-O-(2-methoxyethyl), 2’-O-(2-methoxyethyl), and any combinations thereof. For example, TT (UU) can be an overhang sequence for either end on either strand. The overhang can form a mismatch with the target mRNA, or it can be complementary to the gene sequences being targeted, or it can be another sequence.

[0107] The 5’- or 3 ’-overhangs at the sense strand, antisense strand, or both strands of the dsRNA agent may be phosphorylated. In some embodiments, the overhang region - 34 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTcontains two nucleotides having a phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate between the two nucleotides, where the two nucleotides can be the same or different. In one embodiment, the overhang is present at the 3’ end of the sense strand, antisense strand, or both strands. In one embodiment, this 3’-overhang is present in the antisense strand. In one embodiment, this 3’ -overhang is present in the sense strand. In some embodiments the siRNA molecule comprises a vinyl phosphonate modification attached to the sense strand. In some embodiments, the siRNA molecule comprises a vinyl phosphonate modification attached to the antisense strand. In some embodiments, the vinyl phosphonate modification is attached to the 5’ or the 3’ end of one or both of the sense strand or the antisense strand. In some embodiments, the vinyl phosphonate modification is attached to the 5’ end of the sense strand. In some embodiments, the vinyl phosphonate modification is attached to the 3’ end of the sense strand. In some embodiments, the vinyl phosphonate modification is attached to the 5’ end of the antisense strand. In some embodiments, the vinyl phosphonate modification is attached to the 3’ end of the antisense strand.

[0108] The dsRNA agent may comprise only a single overhang, which can strengthen the interference activity of the dsRNA without affecting its overall stability. For example, the single-stranded overhang is located at the 3 ’-terminal end of the sense strand or, alternatively, at the 3 ’-terminal end of the antisense strand. The dsRNA may also have a blunt end, located at the 5’ end of the antisense strand (or the 3’ end of the sense strand) or vice versa.Generally, the antisense strand of the dsRNA has a nucleotide overhang at the 3’ end, and the 5’ end is blunt. While not bound by theory, the asymmetric blunt end at the 5’ end of the antisense strand and the overhang at the 3' end of the antisense strand favor the guide strand loading into the RNA induced silencing complex (RISC). A single overhang may comprise more than one nucleotide. For example, the single overhang comprises at least two, three, four, five, six, seven, eight, nine, or ten nucleotides.

[0109] In some embodiments, the dsRNA agent may also have two blunt ends, at both ends of the dsRNA duplex.

[0110] In some embodiments, every nucleotide in the sense strand and antisense strand of the dsRNA agent may be modified. Each nucleotide may be modified with the same or different modification, which can include one or more alterations of one or both of the non-linking phosphate oxygens and / or of one or more of the linking phosphate oxygens; alteration of a constituent of the ribose sugar, e.g., of the 2’-hydroxyl on the ribose sugar; wholesale replacement of the phosphate moiety with “dephospho” linkers; modification or - 35 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTreplacement of a naturally occurring base; and replacement or modification of the ribosephosphate backbone.

[0111] In some embodiments, all or some of the bases in a 3’ or 5’ overhang may be modified, e.g., with a modification described herein. Modifications can include, e.g., the use of modifications at the 2' position of the ribose sugar with modifications that are known in the art, e.g., the use of deoxyribonucleotides, 2'-deoxy-2'-fluoro (2'-F) or 2'-O-methyl (2'-0Me) modified instead of the ribosugar of the nucleobase, and modifications in the phosphate group, e.g., phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, or mesyl phosphoramidate modifications. Overhangs need not be homologous with the target sequence.

[0112] In some embodiments, each residue of the sense strand and antisense strand is independently modified with LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-methyl, 2'-O-allyl, 2'-C-allyl, 2'-deoxy, or 2'-fluoro. The strands can contain more than one modification. In one embodiment, each residue of the sense strand and antisense strand is independently modified with 2'-O-methyl or 2'-fluoro.

[0113] In some embodiments, at least two different modifications are typically present on the sense strand and antisense strand. Those two modifications may be the 2'-deoxy, 2'-O-methyl or 2'-fluoro modifications, acyclic nucleotides, or others.

[0114] In one embodiment, the sense strand and antisense strand each comprises two differently modified nucleotides selected from 2'-fluoro, 2'-O-methyl, or 2'-deoxy.

[0115] The dsRNA agent may further comprise at least one phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate internucleotide linkage. The phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both in any position of the strand. For instance, the internucleotide linkage modification may occur on every nucleotide on the sense strand and / or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand or antisense strand; or the sense strand or antisense strand comprises both intemucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand.- 36 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0116] In some embodiments, the dsRNA agent comprises the phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate internucleotide linkage modification in the overhang region. For example, the overhang region comprises two nucleotides having a phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate internucleotide linkage between the two nucleotides. Internucleotide linkage modifications also may be made to link the overhang nucleotides with the terminal paired nucleotides within the duplex region. For example, at least 2, 3, 4, or all the overhang nucleotides may be linked through phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate intemucleotide linkage, and optionally, there may be additional phosphorothioate, phosphorodithoate, phosphonate, phosphoramidate, mesyl phosphoramidate, or methylphosphonate internucleotide linkages linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleotide linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is a paired nucleotide next to the overhang nucleotide. In some embodiments, these terminal three nucleotides may be at the 3' end of the antisense strand.

[0117] In some embodiments, the dsRNA agent is linked by a modified base or nucleoside analogue as described in U. S. Patent No. 7,427,672, which is incorporated herein by reference. In some embodiments, the modified base or nucleoside analogue is referred to as the linker or L in formulas described herein.

[0118] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and a salt thereof:z \(Chemical Formula I)

[0119] where Base represents an aromatic heterocyclic group or aromatic hydrocarbon ring group optionally having a substituent, Ri and R2 are identical or different, and each represent a hydrogen atom, a protective group for a hydroxyl group for nucleic acid synthesis, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group, a sulfonyl group, a silyl group, a phosphate group, a phosphate group protected with a protective group for nucleic acid synthesis, or — P(R4)Rs where R4 and Rs are identical or different, and each represent a hydroxyl group, a hydroxyl group protected with a- 37 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTprotective group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted by an alky group having 1 to 5 carbon atoms, and X denotes OMe or F.

[0120] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein Ri is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, or a silyl group.

[0121] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein Ri is a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, a trityl group, a dimethoxytrityl group, a monomethoxytrityl group, or a tert-butyldiphenylsilyl group.

[0122] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein R2 is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, a silyl group, a phosphoroamidite group, a phosphonyl group, a phosphate group, or a phosphate group protected with a protective group for nucleic acid synthesis.

[0123] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein R2 is a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, a tert-butyldiphenylsilyl group, — P(OC2H4CN)(N(i-Pr)?), — P(OCHs)(N(i-Pr)2), a phosphonyl group, or a 2-chlorophenyl- or 4-chlorophenylphosphate group.

[0124] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein Base is a purin-9-yl group, a 2-oxopyrimidin-l-yl group, or a purin-9-yl group or a 2-oxopyrimidin-l-yl group having a substituent selected from the following a groups: A hydroxyl group, a hydroxyl group protected with a protective group for nucleic acid synthesis, an alkoxy group having 1- 38 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTto 5 carbon atoms, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, and a halogen atom.

[0125] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula I and salts thereof, wherein Base is 6-aminopurin-9-yl (i.e., adeninyl), 6-aminopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2,6-diaminopurin-9-yl, 2-amino-6-chloropurin-9-yl, 2-amino-6-chloropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-fluoropurin-9-yl, 2-amino-6-fluoropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-bromopurin-9-yl, 2-amino-6-bromopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), 2-amino-6-hydroxypurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 6-amino-2-methoxypurin-9-yl, 6-amino-2-chloropurin-9-yl, 6-amino-2-fluoropurin-9-yl, 2,6-dimethoxypurin-9-yl, 2,6-dichloropurin-9-yl, 6-mercaptopurin-9-yl, 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl (i.e., cytosinyl), 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-oxo-4-amino-5-fluoro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-methoxy- 1,2-dihydropyrimidin- 1 -yl. 2-oxo-4-mercapto- 1,2-dihydropyrimidin- 1 -yl, 2-oxo-4-hydroxy-l,2-dihydropyrimidin-l-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-l,2-dihydropyrimidin-l-yl (i.e., thyminyl), 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl (i.e., 5-methylcytosinyl), or 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis.

[0126] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and a salt thereof:- 39 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT- OR3 (Chemical Formula IB)

[0127] where Base represents an aromatic heterocyclic group or aromatic hydrocarbon ring group optionally having a substituent, Ri and R2 are identical or different, and each represent a hydrogen atom, a protective group for a hydroxyl group for nucleic acid synthesis, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group, a sulfonyl group, a silyl group, a phosphate group, a phosphate group protected with a protective group for nucleic acid synthesis, or — P(R4)Rs where R4 and Rs are identical or different, and each represent a hydroxyl group, a hydroxyl group protected with a protective group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted by an alky group having 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group, a sulfonyl group, or a functional molecule unit substituent, and m denotes an integer of 0 to 2, and n denotes an integer of 0 to 3. In some embodiments, m and n are 0.

[0128] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein Ri is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, or a silyl group.

[0129] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein Ri is a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a- 40 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTbenzyl group, a p-methoxybenzyl group, a trityl group, a dimethoxytrityl group, a monomethoxytrityl group, or a tert-butyldiphenylsilyl group.

[0130] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein Rz is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, a silyl group, a phosphoroamidite group, a phosphonyl group, a phosphate group, or a phosphate group protected with a protective group for nucleic acid synthesis.

[0131] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein R2 is a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, a tert-butyldiphenylsilyl group, — P(OCzH4CN)(N(i-Pr)z), — P(OCH3)(N(i-Pr)2), a phosphonyl group, or a 2-chlorophenyl- or 4-chlorophenylphosphate group.

[0132] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein R3 is a hydrogen atom, a phenoxyacetyl group, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 1 to 5 carbon atoms, an aryl group having 6 to 14 carbon atoms, a methyl group substituted by one to three aryl groups, a lower aliphatic or aromatic sulfonyl group such as a methanesulfonyl group or a p-toluenesulfonyl group, an aliphatic acyl group having 1 to 5 carbon atoms such as an acetyl group, or an aromatic acyl group such as a benzoyl group.

[0133] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein the functional molecule unit substituent as R3 is a fluorescent or chemiluminescent labeling molecule, a nucleic acid incision activity functional group, or an intracellular or nuclear transfer signal peptide.

[0134] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein Base is a purin-9-yl group, a 2-oxopyrimidin-l-yl group, or a purin-9-yl group or a 2-oxopyrimidin-l-yl group having a substituent selected from the following a groups: a hydroxyl group, a hydroxyl group protected with a protective group for nucleic acid synthesis, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an - 41 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTamino group protected with a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, and a halogen atom.

[0135] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein Base is 6-aminopurin-9-yl (z.e., adeninyl), 6-aminopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2,6-diaminopurin-9-yl, 2-amino-6-chloropurin-9-yl, 2-amino-6-chloropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-fluoropurin-9-yl, 2-amino-6-fluoropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-bromopurin-9-yl, 2-amino-6-bromopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), 2-amino-6-hydroxypurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 6-amino-2-methoxypurin-9-yl, 6-amino-2-chloropurin-9-yl, 6-amino-2-fluoropurin-9-yl, 2,6-dimethoxypurin-9-yl, 2,6-dichloropurin-9-yl, 6-mercaptopurin-9-yl, 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl (i.e., cytosinyl), 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-oxo-4-amino-5-fluoro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-methoxy-1,2-dihydropyrimidin-l -yl, 2-oxo-4-mercapto-l,2-dihydropyrimidin- 1 -yl, 2-oxo-4-hydroxy-l,2-dihydropyrimidin-l-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-l,2-dihydropyrimidin- 1 -yl (i.e., thyminyl), 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl (i.e., 5-methylcytosinyl), or 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis.

[0136] In some embodiments, the modified base or nucleoside analogue has the structure as shown in Chemical Formula IB and salts thereof, wherein m is 0, and n is i.

[0137] In some embodiments, the modified base or nucleoside analogue is a DNA oligonucleotide or RNA oligonucleotide analogue, containing one or two or more of one or more types of unit structures of nucleoside analogues having the structure as shown in Chemical Formula II, or a pharmacologically acceptable salt thereof, provided that a form of linking between respective nucleosides in the oligonucleotide analogue may contain one or two or more phosphorothioate bonds [— OP(O)(S )O— ], phosphorodithioate bonds [-O2PS2- ], phosphonate bonds [— PO(OH)2-], phosphoramidate bonds [-O=P(OH)2— ], or mesyl - 42 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTphosphoramidate bonds [— OP(O)(N)(SO2)(CH3)O-] aside from a phosphodiester bond [— OP(O2-)O—] identical with that in a natural nucleic acid, and if two or more of one or more types of these structures are contained, Base may be identical or different between these structures:(Chemical Formula II)

[0138] where Base represents an aromatic heterocyclic group or aromatic hydrocarbon ring group optionally having a substituent, and X denotes OMe or F.

[0139] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula II, wherein Base is a purin- 9-yl group, a 2-oxopyrimidin-l-yl group, or a purin-9-yl group or a 2-oxopyrimidin-l-yl group having a substituent selected from the following a group: a hydroxyl group, a hydroxyl group protected with a protective group for nucleic acid synthesis, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, and a halogen atom.

[0140] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula II, wherein Base is 6-aminopurin-9-yl (i.e., adeninyl), 6-aminopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2,6-diaminopurin-9-yl, 2-amino-6-chloropurin-9-yl, 2-amino-6-chloropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-fluoropurin-9-yl, 2-amino-6-fluoropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-bromopurin-9-yl, 2-amino-6-bromopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), 2-amino-6-hydroxypurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 6-amino-2-methoxypurin-9-yl, 6-amino-2-chloropurin-9-yl, 6-amino-2-fluoropurin-9-yl, 2,6-dimethoxypurin-9-yl, 2,6-dichloropurin-9-yl, 6-mercaptopurin-9-yl, 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl (i.e., cytosinyl), 2-oxo-4-amino-l,2-- 43 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTdihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-oxo-4-amino-5-fluoro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-l-yl group having the amino group protected with a protective group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-methoxy- 1,2-dihydropyrimidin- 1 -yl, 2-oxo-4-mercapto- 1,2-dihydropyrimidin- 1 -yl, 2-oxo-4-hydroxy-l,2-dihydropyrimidin-l-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-l,2-dihydropyrimidin-l-yl (z.e., thyminyl), 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl (i.e., 5-methylcytosinyl), or 4-amino-5-methyl-2-oxo -1,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis.

[0141] In some embodiments, the modified base or nucleoside analogue is a DNA oligonucleotide or RNA oligonucleotide analogue, containing one or two or more of one or more types of unit structures of nucleoside analogues having the structure as shown in Chemical Formula IIB, or a pharmacologically acceptable salt thereof, provided that a form of linking between respective nucleosides in the oligonucleotide analogue may contain one or two or more phosphorothioate bonds [— OP(O)(S )O— ], phosphorodithioate bonds [-O2PS2- ], phosphonate bonds [— PO(OH)2-], phosphoramidate bonds [--O=P(OH)2— ], or mesyl phosphoramidate bonds [— OP(O)(N)(SO2)(CH3)O-] aside from a phosphodiester bond [— OP(O2')O— ] identical with that in a natural nucleic acid, and if two or more of one or more types of these structures are contained, Base may be identical or different between these structures:O(Chemical Formula IIB)

[0142] where Base represents an aromatic heterocyclic group or aromatic hydrocarbon ring group optionally having a substituent, Rs represents a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group, a sulfonyl group, a silyl group, or a functional molecule unit substituent, and m- 44 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTdenotes an integer of 0 to 2, and n denotes an integer of 0 to 3. In some embodiments, m and n are 0.

[0143] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein Ri is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, or a silyl group.

[0144] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein Ri is a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, a trityl group, a dimethoxytrityl group, a monomethoxytrityl group, or a tert-butyldiphenylsilyl group.

[0145] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein R2 is a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an aliphatic or aromatic sulfonyl group, a methyl group substituted by one to three aryl groups, a methyl group substituted by one to three aryl groups having an aryl ring substituted by a lower alkyl, lower alkoxy, halogen, or cyano group, a silyl group, a phosphoroamidite group, a phosphonyl group, a phosphate group, or a phosphate group protected with a protective group for nucleic acid synthesis.

[0146] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein R2 is a hydrogen atom, an acetyl group, a benzoyl group, a benzyl group, a p-methoxybenzyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a tert-butyldiphenylsilyl group, - P(OC2H4CN)(N(i-Pr)2), -P(OCH3)(N(i-Pr)2), a phosphonyl group, or a 2-chlorophenyl- or 4-chlorophenylphosphate group.

[0147] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein R3 is a hydrogen atom, a phenoxyacetyl group, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 1 to 5 carbon atoms, an aryl group having 6 to 14 carbon atoms, a methyl group substituted by one to three aryl groups, a lower aliphatic or aromatic sulfonyl group such as a methanesulfonyl group or a p-toluenesulfonyl group, an aliphatic acyl group- 45 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENThaving 1 to 5 carbon atoms such as an acetyl group, or an aromatic acyl group such as a benzoyl group.

[0148] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein the functional molecule unit substituent as R3 is a fluorescent or chemiluminescent labeling molecule, a nucleic acid incision activity functional group, or an intracellular or nuclear transfer signal peptide.

[0149] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein Base is a purin- 9-yl group, a 2-oxopyrimidin-l-yl group, or a purin- 9-yl group or a 2-oxopyrimidin-l-yl group having a substituent selected from the following a groups: A hydroxyl group, a hydroxyl group protected with a protective group for nucleic acid synthesis, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, and a halogen atom.

[0150] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein Base is 6-aminopurin-9-yl (i.e., adeninyl), 6-aminopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2,6-diaminopurin-9-yl, 2-amino-6-chloropurin-9-yl, 2-amino-6-chloropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-fluoropurin-9-yl, 2-amino-6-fluoropurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-bromopurin-9-yl, 2-amino-6-bromopurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), 2-amino-6-hydroxypurin-9-yl having the amino group protected with a protective group for nucleic acid synthesis, 6-amino-2-methoxypurin-9-yl, 6-amino-2-chloropurin-9-yl, 6-amino-2-fluoropurin-9-yl, 2,6-dimethoxypurin-9-yl, 2,6-dichloropurin-9-yl, 6-mercaptopurin-9-yl, 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl i.e., cytosinyl), 2-oxo-4-amino-l,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis, 2-oxo-4-amino-5-fluoro-l,2-dihydropyrimidin-l-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-l-yl group having the amino group protected with a protective group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-l,2-dihydropyrimidin-l-yl, 2-oxo-4- - 46 - TPTS / 200322635 1Attorney Docket No. ROO-037WO PATENTmethoxy- 1,2-dihydropyrimidin- 1 -yl, 2-oxo-4-mercapto- 1,2-dihydropyrimidin- 1 -yl, 2-oxo-4-hydroxy-l,2-dihydropyrimidin-l-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-l,2-dihydropyrimidin-l-yl (i.e., thyminyl), 4-amino-5-methyl-2-oxo-l,2-dihydropyrimidin-l-yl (i.e., 5-methylcytosinyl), or 4-amino-5-methyl-2-oxo -1,2-dihydropyrimidin-l-yl having the amino group protected with a protective group for nucleic acid synthesis.

[0151] In some embodiments, the oligonucleotide analogue or the pharmacologically acceptable salt thereof has the structure as shown in Chemical Formula IIB, wherein m is 0, and n is 1.

[0152] In some embodiments, the dsRNA agent comprises mismatch(es) with the target, within the duplex, or combinations thereof. The mismatch can occur in the overhang region or the duplex region. The base pair can be ranked on the basis of their propensity to promote dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, though next neighbor or similar analysis can also be used). In terms of promoting dissociation: A: U is preferred over G: C; G: U is preferred over G: C; and I: C is preferred over G: C (I=inosine). Mismatches, e.g., non-canonical or other than canonical pairings (as described elsewhere herein) are preferred over canonical (A: T, A: U, G: C) pairings; and pairings which include a universal base are preferred over canonical pairings.

[0153] In some embodiments, the dsRNA agent can comprise a phosphorus-containing group at the 5'-end of the sense strand or antisense strand. The 5'-end phosphorus-containing group can be 5’-end phosphate (5'-P), 5'-end phosphorothioate (5'-PS), 5'-end phosphorodithioate (5'-PS2), 5'-end vinyl phosphonate (5'-VP), 5'-end methylphosphonate (MePhos), 5' -end mesyl phosphoramidate (5’MsPA), or 5'-deoxy-5'-C-malonyl. When the 5'-end phosphorus-containing group is 5'-end vinyl phosphonate (5'-VP), the 5'- VP can be either 5 -E-VP isomer, such as trans-vinyl phosphate or cis-vinyl phosphate, or mixtures thereof. Representative structures of these modifications can be found in, for example, U. S. Patent No. 10,233,448, which is hereby incorporated by reference in its entirety.

[0154] In some embodiments, nucleotide analogues or synthetic nucleotide base comprise a nucleic acid with a modification at a 2' hydroxyl group of the ribose moiety. In some instances, the modification includes an H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, wherein R is an alkyl moiety. Exemplary alkyl moiety includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, Ci-Cio chain lengths both linear and branched. In some instances, the alkyl moiety further comprises a modification. In some instances, the modification comprises an azo group, a keto group, an aldehyde group, a - 47 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTcarboxyl group, a nitro group, a nitroso, group, a nitrile group, a heterocycle (e.g., imidazole, hydrazine or hydroxylamino) group, an isocyanate or cyanate group, or a sulfur containing group (e.g., sulfoxide, sulfone, sulfide, and disulfide). In some instances, the alkyl moiety further comprises additional hetero atom such as O, S, N, Se and each of these hetero atoms can be further substituted with alky groups as described above. In some instances, the carbon of the heterocyclic group is substituted by a nitrogen, oxygen or sulfur. In some instances, the heterocyclic substitution includes but is not limited to, morpholino, imidazole, and pyrrolidino.

[0155] In some instances, the modification at the 2’ hydroxyl group is a 2’-O-methyl modification or a 2’ -O-methoxy ethyl (2'-0-M0E) modification. Exemplary chemical structures of a 2’-O-methyl modification of an adenosine molecule and 2’ O-methoxyethyl modification of an uridine are illustrated below in chemical formulas IIIA and IIIB.2'-O-methoxyethyl uridine Chemical formula IIIA Chemical formula IIIB

[0156] In some instances, the modification at the 2’ hydroxyl group is a 2’-O-aminopropyl modification in which an extended amine group comprising a propyl linker binds the amine group to the 2’ oxygen. In some instances, this modification neutralizes the phosphate derived overall negative charge of the oligonucleotide molecule by introducing one positive charge from the amine group per sugar and thereby improves cellular uptake properties due to its zwitterionic properties. An exemplary chemical structure of a 2’-O-aminopropyl nucleoside phosphoramidite is illustrated below in chemical formula IV.- 48 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT2'-O-aminopropyl nucleoside phosphoramiditeChemical formula IV

[0157] In some instances, the modification at the 2’ hydroxyl group is a locked or bridged ribose modification (e.g., locked nucleic acid or LNA) in which the oxygen molecule bound at the 2’ carbon is linked to the 4’ carbon by a methylene group, thus forming a 2'- C,4'-C-oxy- methylene-linked bicyclic ribonucleotide monomer. Exemplary representations of the chemical structure of LNA are illustrated below. The representation shown to the left highlights the chemical connectivities of an LNA monomer. The representation shown to the right highlights the locked 3'-endo (3E) conformation of the furanose ring of an LNA monomer (Chemical formulas VA and VB).O^=P - O’LNA (Locked Nucleic Acids)Chemical Formula VA Chemical Formula VB

[0158] In some instances, the modification at the 2’ hydroxyl group comprises ethylene nucleic acids (ENA) such as for example 2’ -4’ -ethylene -bridged nucleic acid, which locks the sugar conformation into a C3’-endo sugar puckering conformation. ENA are part of - 49 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe bridged nucleic acids class of modified nucleic acids that also comprises LNA.Exemplary chemical structures of the ENA and bridged nucleic acids are illustrated below in chemical formula VIA-D.3’-amiBO-2 -BNA 2 ’-BNA-2-pyridoBeChemical formula VIA Chemical formula VIB2%4’-ENA 2 ’~B A-1 soqu oloneChemical formula VIC Chemical formula VID

[0159] In some embodiments, additional modifications at the 2’ hydroxyl group include 2'- deoxy, 2’-deoxy-2’-fluoro, 2’-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O- DMAOE), 2'-O-dimethylaminopropyl (2’-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2'-O- DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA).

[0160] In some embodiments, nucleotide analogues comprise modified bases such as, but not limited to, 5-propynyluridine, 5-propynylcytidine, 6-methyladenine, 6-methylguanine, N, N, -dimethyladenine, 2-propyladenine, 2-propylguanine, 2-aminoadenine, 1 -methylinosine, 3- methyluridine, 5-methylcytidine, 5-methyluridine and other nucleotides having a modification at the 5 position, 5- (2- amino) propyl uridine, 5-halocytidine, 5-halouridine, 4-acetylcytidine, 1 -methyladenosine, 2-methyladenosine, 3 -methylcytidine, 6-methyluridine, 2-methylguanosine, 7-methylguanosine, 2,2-dimethylguanosine, 5-methylaminoethyluridine, 5-methyl oxyuridine, deazanucleotides such as 7-deaza- adenosine, 6-azouridine, 6-azocytidine,- 50 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT6-azothymidine, 5-methyl-2-thiouridine, other thio bases such as 2-thiouridine and 4-thiouridine and 2-thiocytidine, dihydrouridine, pseudouridine, queuosine, archaeosine, naphthyl and substituted naphthyl groups, any O-and N-alkylated purines and pyrimidines such as N6-methyladenosine, 5-methylcarbonylmethyluridine, uridine 5-oxyacetic acid, pyridine-4-one, pyridine-2-one, phenyl and modified phenyl groups such as aminophenol or 2,4, 6-trimethoxy benzene, modified cytosines that act as G-clamp nucleotides, 8-substituted adenines and guanines, 5-substituted uracils and thymines, azapyrimidines, carboxyhydroxyalkyl nucleotides, carboxyalkylaminoalkyl nucleotides, and alkylcarbonylalkylated nucleotides. Modified nucleotides also include those nucleotides that are modified with respect to the sugar moiety, as well as nucleotides having sugars or analogs thereof that are not ribosyl. For example, the sugar moieties, in some cases are or be based on, mannoses, arabinoses, glucopyranoses, galactopyranoses, 4'-thioribose, and other sugars, heterocycles, or carbocycles. The term nucleotide also includes what are known in the art as universal bases. By way of example, universal bases include but are not limited to 3-nitropyrrole, 5-nitroindole, or nebularine.

[0161] In some embodiments, nucleotide analogues further comprise morpholines, peptide nucleic acids (PNAs), methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, l’,5’-anhydrohexitol nucleic acids (HNAs), or a combination thereof. Morpholino or phosphorodiamidate morpholino oligo (PMO) comprises synthetic molecules whose structure mimics natural nucleic acid structure by deviates from the normal sugar and phosphate structures. In some instances, the five-member ribose ring is substituted with a six member morpholino ring containing four carbons, one nitrogen and one oxygen. In some cases, the ribose monomers are linked by a phosphorodiamidate group instead of a phosphate group. In such cases, the backbone alterations remove all positive and negative charges making morpholines neutral molecules capable of crossing cellular membranes without the aid of cellular delivery agents such as those used by charged oligonucleotides.- 51 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTMorpholinoChemical formula VII

[0162] In some embodiments, peptide nucleic acid (PNA) does not contain sugar ring or phosphate linkage and the bases are attached and appropriately spaced by oligoglycine-like molecules, therefore, eliminating a backbone charge.BPNAChemical formula VIII

[0163] In some embodiments, one or more modifications optionally occur at the internucleotide linkage. In some instances, modified internucleotide linkage include, but is not limited to, phosphorothioates,, mesyl phosphoramidate, phosphorodithioates, methylphosphonates, 5'-alkylenephosphonates, 5’-methylphosphonate, 3’-alkylene phosphonates, borontrifluoridates, borano phosphate esters and selenophosphates of 3'-5' linkage or 2'-5' linkage, phosphotriesters, thionoalkylphosphotriesters, hydrogen phosphonate linkages, alkyl phosphonates, alkylphosphonothioates, arylphosphonothioates, phosphoroselenoates, phosphorodiselenoates, phosphinates, phosphoramidates, 3'-alkylphosphoramidates, aminoalkylphosphoramidates, thionophosphoramidates, phosphoropiperazidates, phosphoroanilothioates, phosphoroanilidates, ketones, sulfones, sulfonamides, carbonates, carbamates, methylenehydrazos, methylenedimethylhydrazos, formacetals, thioformacetals, oximes, methyleneiminos, methylenemethyliminos, thioamidates, linkages with riboacetyl groups, aminoethyl glycine, silyl or siloxane linkages,- 52 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTalkyl or cycloalkyl linkages with or without heteroatoms of, for example, 1 to 10 carbons that are saturated or unsaturated and / or substituted and / or contain heteroatoms, linkages with morpholino structures, amides, polyamides wherein the bases are attached to the aza nitrogens of the backbone directly or indirectly, and combinations thereof. Phosphorothioate antisense oligonucleotides (PS ASO) are antisense oligonucleotides comprising a phosphorothioate linkage. Mesyl phosphoramidate antisense oligonucleotides (MsPA ASO) are antisense oligonucleotides comprising a mesyl phosphoramidate linkage.

[0164] In some instances, the modification is a methyl or thiol modification such as methylphosphonate, mesyl phosphoramidate, or thiolphosphonate modification. In some instances, a modified nucleotide includes, but is not limited to, 2'-fluoro N3- P5’-phosphoramidites.

[0165] In some instances, a modified nucleotide includes, but is not limited to, hexitol nucleic acid (or 1’, 5’-anhydrohexitol nucleic acids (HNA)).

[0166] In some embodiments, one or more modifications further optionally include modifications of the ribose moiety, phosphate backbone and the nucleoside, or modifications of the nucleotide analogues at the 3’ or the 5’ terminus. For example, the 3’ terminus optionally includes a 3’ cationic group, or by inverting the nucleoside at the 3’ -terminus with a 3’ -3’ linkage. In another alternative, the 3’-terminus is optionally conjugated with an aminoalkyl group, e.g., a 3’ C5-aminoalkyl dT. In an additional alternative, the 3’-terminus is optionally conjugated with an abasic site, e.g., with an apurinic or apyrimidinic site. In some instances, the 5’ -terminus is conjugated with an aminoalkyl group, e.g., a 5’-O-alkylamino substituent. In some cases, the 5’-terminus is conjugated with an abasic site, e.g., with an apurinic or apyrimidinic site.

[0167] In some embodiments, the oligonucleotide molecule comprises one or more of the synthetic nucleotide analogues described herein. In some instances, the oligonucleotide molecule comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, or more of the synthetic nucleotide analogues described herein. In some embodiments, the synthetic nucleotide analogues include 2’-O-methyl, 2’-O-methoxyethyl (2’-0-M0E), 2'-O-aminopropyl, 2’-deoxy, 2’-deoxy-2’-fluoro, 2’-O-aminopropyl (2’-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modified, LNA, ENA, PNA, HNA, morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, or a combination thereof. In some instances, the oligonucleotide molecule comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,- 53 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT13, 14, 15, 16, 17, 18, 20, 25, or more of the synthetic nucleotide analogues selected from 2’-O-methyl, 2’ -O-methoxyethyl (2’-0-M0E), 2’ -O-aminopropyl, 2'-deoxy, 2’-deoxy-2'-fluoro, 2'-O-aminopropyl (2-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2’-O-dimethylaminopropyl (2-O-DMAP), 2’-O- dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modified, LNA, ENA, PNA, HNA, morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, or a combination thereof. In some instances, the oligonucleotide molecule comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, or more of 2’-O-methyl modified nucleotides. In some instances, the oligonucleotide molecule comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, or more of 2’-O- methoxyethyl (2’-0-M0E) modified nucleotides. In some instances, the oligonucleotide molecule comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, or more of thiolphosphonate nucleotides.

[0168] In some instances, the oligonucleotide molecule comprises at least one of: from about 5% to about 100% modification, from about 10% to about 100% modification, from about 20% to about 100% modification, from about 30% to about 100% modification, from about 40% to about 100% modification, from about 50% to about 100% modification, from about 60% to about 100% modification, from about 70% to about 100% modification, from about 80% to about 100% modification, and from about 90% to about 100% modification. In some instances, the oligonucleotide molecule comprises 100% modification.

[0169] In some cases, the oligonucleotide molecule comprises at least one of: from about 10% to about 90% modification, from about 20% to about 90% modification, from about 30% to about 90% modification, from about 40% to about 90% modification, from about 50% to about 90% modification, from about 60% to about 90% modification, from about 70% to about 90% modification, and from about 80% to about 100% modification.

[0170] In some cases, the oligonucleotide molecule comprises at least one of: from about 10% to about 80% modification, from about 20% to about 80% modification, from about 30% to about 80% modification, from about 40% to about 80% modification, from about 50% to about 80% modification, from about 60% to about 80% modification, and from about 70% to about 80% modification.

[0171] In some instances, the oligonucleotide molecule comprises at least one of: from about 10% to about 70% modification, from about 20% to about 70% modification, from about 30% to about 70% modification, from about 40% to about 70% modification, from about 50% to about 70% modification, and from about 60% to about 70% modification.- 54 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0172] In some instances, the oligonucleotide molecule comprises at least one of: from about 10% to about 60% modification, from about 20% to about 60% modification, from about 30% to about 60% modification, from about 40% to about 60% modification, and from about 50% to about 60% modification.

[0173] In some cases, the oligonucleotide molecule comprises at least one of: from about 10% to about 50% modification, from about 20% to about 50% modification, from about 30% to about 50% modification, and from about 40% to about 50% modification.

[0174] In some cases, the oligonucleotide molecule comprises at least one of: from about 10% to about 40% modification, from about 20% to about 40% modification, and from about 30% to about 40% modification.

[0175] In some cases, the oligonucleotide molecule comprises at least one of: from about 10% to about 30% modification, and from about 20% to about 30% modification.

[0176] In some cases, the oligonucleotide molecule comprises from about 10% to about 20% modification.

[0177] In some cases, the oligonucleotide molecule comprises from about 15% to about 90%, from about 20% to about 80%, from about 30% to about 70%, or from about 40% to about 60% modifications.

[0178] In additional cases, the oligonucleotide molecule comprises at least about 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% modifications.

[0179] In some embodiments, the oligonucleotide molecule comprises at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 modifications.

[0180] In some instances, the oligonucleotide molecule comprises at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 modified nucleotides.

[0181] In some instances, from about 5 to about 100% of the oligonucleotide molecule comprise the synthetic nucleotide analogues described herein. In some instances, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,- 55 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT80%, 85%, 90%, 95% or 100% of the oligonucleotide molecule comprise the synthetic nucleotide analogues described herein. In some instances, about 5% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 10% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 15% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 20% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 25% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 30% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 35% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 40% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 45% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 50% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 55% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 60% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 65% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 70% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 75% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 80% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 85% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 90% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 95% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 96% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 97% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 98% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 99% of the oligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some instances, about 100% of the - 56 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENToligonucleotide molecule comprises the synthetic nucleotide analogues described herein. In some embodiments, the synthetic nucleotide analogues include 2’-O-methyl, 2’-O-methoxyethyl (2’-O-MOE), 2’-O-aminopropyl, 2’-deoxy, 2’-deoxy-2'-fluoro, 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2-0-dimethylaminopropyl (2-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modified, LNA, ENA, PNA, HNA, morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, or a combination thereof.

[0182] In some embodiments, the oligonucleotide molecule comprises from about 1 to about 25 modifications in which the modification comprises an synthetic nucleotide analogues described herein. In some embodiments, the oligonucleotide molecule comprises about 1 modification in which the modification comprises a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 2 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 3 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 4 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 5 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 6 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 7 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 8 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 9 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 10 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 11 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 12 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some- 57 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTembodiments, the oligonucleotide molecule comprises about 13 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 14 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 15 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 16 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 17 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 18 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 19 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 20 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 21 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 22 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 23 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 24 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 25 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 26 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 27 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 28 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 29 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some- 58 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTembodiments, the oligonucleotide molecule comprises about 30 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 31 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 32 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 33 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 34 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 35 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 36 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 37 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 38 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 39 modifications in which the modifications comprise a synthetic nucleotide analogue described herein. In some embodiments, the oligonucleotide molecule comprises about 40 modifications in which the modifications comprise a synthetic nucleotide analogue described herein.

[0183] In some embodiments, an oligonucleotide molecule is assembled from two separate polynucleotides wherein one polynucleotide comprises the sense strand and the second polynucleotide comprises the antisense strand of the oligonucleotide molecule. In other embodiments, the sense strand is connected to the antisense strand via a linker molecule, which in some instances is a polynucleotide linker or a non-nucleotide linker.

[0184] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, wherein pyrimidine nucleotides in the sense strand comprises 2'-O-methylpyrimidine nucleotides and purine nucleotides in the sense strand comprise 2'-deoxy purine nucleotides. In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, wherein pyrimidine nucleotides present in the sense strand comprise 2'-deoxy-2'-fluoro pyrimidine nucleotides and wherein purine nucleotides present in the sense strand comprise 2'-deoxy purine nucleotides.- 59 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0185] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, wherein the pyrimidine nucleotides when present in said antisense strand are 2'-deoxy-2'-fluoro pyrimidine nucleotides and the purine nucleotides when present in said antisense strand are 2'-O-methyl purine nucleotides.

[0186] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, wherein the pyrimidine nucleotides when present in said antisense strand are 2'-deoxy-2'-fluoro pyrimidine nucleotides and wherein the purine nucleotides when present in said antisense strand comprise 2'-deoxy-purine nucleotides.

[0187] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, and at least one of sense strand and antisense strands has a plurality of (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, etc.) 2’-O-methyl or 2’ -deoxy-2’ -fluoro modified nucleotides. In some embodiments, at least two, three, four, five, six, or seven out of the a plurality of 2’-O-methyl or 2’ -deoxy-2’ -fluoro modified nucleotides are consecutive nucleotides. In some embodiments, consecutive 2’-O-methyl or 2’ -deoxy-2’ -fluoro modified nucleotides are located at the 5 ’-end of the sense strand and / or the antisense strand. In some embodiments, consecutive 2’-O-methyl or 2’ -deoxy- 2’ -fluoro modified nucleotides are located at the 3’-end of the sense strand and / or the antisense strand. In some embodiments, the sense strand of oligonucleotide molecule includes at least four, at least five, at least six consecutive 2’-O-methyl modified nucleotides at its 5’ end and / or 3’ end, or both. Optionally, in such embodiments, the sense strand of oligonucleotide molecule includes at least one, at least two, at least three, at least four 2’-deoxy-2’-fluoro modified nucleotides at the 3’ end of the at least four, at least five, at least six consecutive 2’-O-methyl modified nucleotides at the polynucleotides’ 5’ end, or at the 5’ end of the at least four, at least five, at least six consecutive 2’-O-methyl modified nucleotides at polynucleotides’ 3’ end. Also optionally, such at least two, at least three, at least four 2’ -deoxy-2’ -fluoro modified nucleotides are consecutive nucleotides.

[0188] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, and at least one of sense strand and antisense strand has 2’-O-methyl modified nucleotide located at the 5’ end of the sense strand and / or the antisense strand. In some embodiments, at least one of sense strand and antisense strands has 2’-O-methyl modified nucleotide located at the 3’ end of the sense strand and / or the antisense strand. In some embodiments, the 2’-O-methyl modified nucleotide located at the 5’ end of the sense strand and / or the antisense strand is a purine nucleotide. In some embodiments, the 2’-O- - 60 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmethyl modified nucleotide located at the 5’ end of the sense strand and / or the antisense strand is a pyrimidine nucleotide.

[0189] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, and one of sense strand and antisense strand has at least two consecutive 2’- deoxy-2’ -fluoro modified nucleotides located at the 5' end, while another strand has at least two consecutive 2’-O-methyl modified nucleotides located at the 5' -end. In some embodiments, where the strand has at least two consecutive 2’ -deoxy-2 ’-fluoro modified nucleotides located at the 5’ end, the strand also includes at least two, at least three consecutive 2’-O-methyl modified nucleotides at the 3’ end of the at least two consecutive 2’-deoxy-2’ -fluoro modified nucleotides. In some embodiments, one of sense strand and antisense strand has at least two, at least three, at least four, at least five, at least six, or at least seven consecutive 2’-O-methyl modified nucleotides that are linked to a 2’ -deoxy-2’ -fluoro modified nucleotide on its 5’ -end and / or 3’ end. In some embodiments, one of sense strand and antisense strand has at least four, at least five nucleotides that have alternating 2’-O-methyl modified nucleotide and 2’ -deoxy-2 ’-fluoro modified nucleotide.

[0190] In some embodiments, the oligonucleotide molecule, such as an siRNA, has the formula as illustrated in Formula IX:N₁N₂N₃N₄N₅N₆N₇N₈N₉N₁₀N₁₁N₁₂N₁₃N₁₄N₁₅N₁₆N₁₇N₁₈N₁₉ Sense-strand (SS) N₁₉N₂₀N₁₈N₁₇N₁₆N₁₅N₁₄N₁₃N₁₂N₁₁N₁₀N₉N₈N₇N₆N₅N₄N₃N₂N₁Antisense-strand (AS)

[0191] wherein each nucleotide represented by N, is independently. A, U, C, or G or a modified nucleotide base, such as those provided for herein. The Ni nucleotides of the sense strand and the antisense strand represent the 5’ end of the respective strands. For clarity, although Formula III utilizes Ni, N2, N3, etc. in both the sense and the antisense strand, the nucleotide bases do not need to be the same and are not intended to be the same. The siRNA that is illustrated in Formula III would be complementary to a target sequence.

[0192] For example, in some embodiments, the sense strand comprises a 2’O-methyl modified nucleotide with a phosphorothioate (PS) modified backbone at Ni and N2, a 2’-fluoro modified nucleotide at N3, N7, Ns, Ns>, N12, and N17, and a 2’O-methyl modified nucleotide at N4, Ns, N&, N10, N11, N13, N14, Nis, Ni6, Nis, and N19.

[0193] In some embodiments, the antisense strand comprises a vinyl phosphonate moiety attached to Ni, a 2’ -fluoro modified nucleotide with a phosphorothioate (PS) modified backbone at N2, a 2’O-methyl modified nucleotide at N3, N4, Ns, Ne, N7, Ns, N9, N10, N11, N12, N13, NIS, Nie, N17, NIS, and N19, a 2’ -fluoro modified nucleotide at N14, and a 2’0-- 61 - TPTS / 200.32263S.1Attorney Docket No. ROO-037WO PATENTmethyl modified nucleotide with a phosphorothioate (PS) modified backbone at N20 and N21. In some embodiments, a vinyl phosphonate moiety is attached to Ni of the antisense strand.

[0194] In some embodiments, an oligonucleotide molecule comprises a sense strand and antisense strand, wherein the sense strand includes a terminal cap moiety at the 5' end, the 3' end, or both of the 5' and 3' ends of the sense strand. In other embodiments, the terminal cap moiety is an inverted deoxy abasic moiety.

[0195] In some embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, wherein the antisense strand comprises a glyceryl modification at the 3' end of the antisense strand.

[0196] In some embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, in which the sense strand comprises one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or about one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3' end, the 5' end, or both of the 3'- and 5'-ends of the sense strand; and in which the antisense strand comprises about 1 to about 10 or more, specifically about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3' end, the 5' end, or both of the 3' and 5' ends of the antisense strand. In other embodiments, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and / or antisense strand are chemically modified with 2'-deoxy, 2'-O-methyl and / or 2'-deoxy-2'-fluoro nucleotides, with or without one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages and / or a terminal cap molecule at the 3' end, the 5' end, or both of the 3' and 5' ends, being present in the same or different strand.

[0197] In some embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, in which the sense strand comprises about 1 to about 25, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more - 62 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTphosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) 2'- deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3’ end, the 5' end, or both of the 3' and 5' ends of the sense strand; and in which the antisense strand comprises about 1 to about 25 or more, for example about 1, 2, 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'- fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3' end, the 5' end, or both of the 3' and 5' ends of the antisense strand. In other embodiments, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and / or antisense strand are chemically-modified with 2'-deoxy, 2'-O-methyl and / or 2'-deoxy-2'-fluoro nucleotides, with or without about 1 to about 25 or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages and / or a terminal cap molecule at the 3' end, the 5' end, or both of the 3' and 5' ends, being present in the same or different strand.

[0198] In some embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, in which the antisense strand comprises one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or about one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides at the 3' end, the 5' end, or both of the 3' and 5' ends of the sense strand and / or antisense strand, and optionally a terminal cap molecule at the 3' end, the 5’ end, or both of the 3' and 5' ends of the sense strand. In some embodiments, the antisense strand comprises about 1 to about 10 or more, specifically about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at - 63 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe 3' end, the 5' end, or both of the 3' and 5' ends of the antisense strand. In other embodiments, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more pyrimidine nucleotides of the sense and / or antisense strand are chemically-modified with 2'-deoxy, 2'-O-methyl and / or 2'-deoxy-2'-fluoro nucleotides, with or without one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages and / or a terminal cap molecule at the 3' end, the 5’ end, or both of the 3' and 5' ends, being present in the same or different strand.

[0199] In some embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, in which the antisense strand comprises about 1 to about 25 or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3' end, the 5' end, or both of the 3’ and 5' ends of the sense strand; and the antisense strand comprises about 1 to about 25 or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'- deoxy-2'-fluoro, and / or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3' end, the 5' end, or both of the 3' and 5' ends of the antisense strand. In other embodiments, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine nucleotides of the sense and / or antisense strand are chemically-modified with 2'-deoxy, 2'-O-methyl and / or 2'-deoxy-2'-fluoro nucleotides, with or without about 1 to about 5, for example about 1, 2, 3, 4, 5 or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages and / or a terminal cap molecule at the 3' end, the 5’ end, or both of the 3' and 5' ends, being present in the same or different strand.

[0200] In some embodiments, an oligonucleotide molecule described herein is a chemically- modified short interfering nucleic acid molecule having about 1 to about 25, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more phosphorothioate, phosphorodithioate, phosphonate, phosphoramidate, or mesyl phosphoramidate internucleotide linkages in each strand of the oligonucleotide molecule. In - 64 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsome embodiments, an oligonucleotide molecule comprises a sense strand and an antisense strand, and the antisense strand comprises a phosphate backbone modification at the 3' end of the antisense strand. Alternatively and / or additionally, an oligonucleotide molecule comprises a sense strand and an antisense strand, and the sense strand comprises a phosphate backbone modification at the 5' end of the antisense strand. In some instances, the phosphate backbone modification is a phosphorothioate. In some instances, the phosphate backbone modification is a phosphorodithioate. In some instances, the phosphate backbone modification is a phosphonate. In some instances, the phosphate backbone modification is a phosphoramidate. In some instances, the phosphate backbone modification is a mesyl phosphoramidate. In some embodiments, the sense or antisense strand has three consecutive nucleosides that are coupled via two phosphorothioate backbone. In some embodiments, the sense or antisense strand has three consecutive nucleosides that are coupled via two phosphorodithioate backbone. In some embodiments, the sense or antisense strand has three consecutive nucleosides that are coupled via two phosphonate backbone. In some embodiments, the sense or antisense strand has three consecutive nucleosides that are coupled via two phosphoramidate backbone. In some embodiments, the sense or antisense strand has three consecutive nucleosides that are coupled via two mesyl phosphoramidate backbone.

[0201] In another embodiment, an oligonucleotide molecule described herein comprises 2'-5' internucleotide linkages. In some instances, the 2'-5' internucleotide linkage(s) is at the 3' end, the 5' end, or both of the 3' and 5' ends of one or both sequence strands. In addition instances, the 2'-5' internucleotide linkage(s) is present at various other positions within one or both sequence strands, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a pyrimidine nucleotide in one or both strands of the oligonucleotide molecule comprise a 2'-5' internucleotide linkage, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a purine nucleotide in one or both strands of the oligonucleotide molecule comprise a 2'-5' internucleotide linkage.

[0202] In some embodiments, an oligonucleotide molecule is a single stranded molecule that mediates RNAi activity in a cell or reconstituted in vitro system, wherein the oligonucleotide molecule comprises a single stranded polynucleotide having complementarity to a target nucleic acid sequence, and wherein one or more pyrimidine nucleotides present in the oligonucleotide molecule are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2'-deoxy-2’-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any - 65 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTpurine nucleotides present in the oligonucleotide molecule are 2'-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2'-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2'-deoxy purine nucleotides), and a terminal cap modification, that is optionally present at the 3' end, the 5' end, or both of the 3' and 5' ends of the antisense sequence, the oligonucleotide molecule optionally further comprising about 1 to about 4 (e.g., about 1, 2, 3, or 4) terminal 2'- deoxynucleotides at the 3' end of the oligonucleotide molecule, wherein the terminal nucleotides further comprise one or more (e.g., 1, 2, 3, or 4) phosphorothioate or mesyl phosphoramidate internucleotide linkages, and wherein the oligonucleotide molecule optionally further comprises a terminal phosphate group, such as a 5'-terminal phosphate group.

[0203] In some cases, one or more of the synthetic nucleotide analogues described herein are resistant toward nucleases, such as ribonuclease (e.g., RNase H), deoxyribonuclease (e.g., DNase), or exonuclease (e.g., 5’-3’ exonuclease and 3’-5’ exonuclease), when compared to natural polynucleic acid molecules and endonucleases. In some instances, synthetic nucleotide analogues comprising 2’-O-methyI, 2’-O-methoxyethyl (2’-O-MOE), 2’-O- aminopropyl, 2'-deoxy, 2’-deoxy-2'-fluoro, 2'-O-aminopropyl (2'-O-AP), 2’-O-dimethylaminoethyl (2’-O-DMAOE), 2’-O-dimethylaminopropyl (2-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2’-O-DMAEOE), or 2’-O-N-methylacetamido (2’-0-NMA) modified, LNA, ENA, PNA, HNA, morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, or combinations thereof are resistant toward nucleases such as ribonuclease (e.g., RNase H), deoxyribonuclease (e.g., DNase), or exonuclease (e.g., 5’-3’ exonuclease and 3’-5’ exonuclease). In some instances, a 2’-O-methyl modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2’-O-methoxyethyl (2’-0-M0E) modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2’-O-aminopropyl modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2'- deoxy modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’ -5’ exonuclease resistance). In some instances, a 2’ -deoxy-2'-fluoro modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’ -5’ exonuclease resistant). In some instances, a 2'-O-aminopropyl (2'-O-AP) modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’ -5’ exonuclease resistant). In some instances, a 2'-O-dimethylaminoethyl (2'-O-DMAOE)- 66 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmodified oligonucleotide molecule is nuclease resistant (e.g., RNase H. DNase, 5’-3' exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2'-O-dimethylaminopropyl (2'-O-DMAP) modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2’-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE) modified oligonucleotide molecule is nuclease resistant e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a 2’-O-N-methylacetamido (2’-O-NMA) modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, an LNA modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5' exonuclease resistant). In some instances, an ENA modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5 ’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, an HNA modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’ -5’ exonuclease resistant). In some instances, morpholines are nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a PNA modified oligonucleotide molecule is resistant to nucleases (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a methylphosphonate modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, a thiolphosphonate modified oligonucleotide molecule is nuclease resistant (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistant). In some instances, an oligonucleotide molecule comprising 2’-fluoro N3-P5’-phosphoramidites is nuclease resistant (e.g., RNase H, DNase, 5’ -3’ exonuclease or 3 ’-5’ exonuclease resistant). In some instances, the 5’ conjugates described herein inhibit 5 ’-3’ exonucleolytic cleavage. In some instances, the 3’ conjugates described herein inhibit 3 ’-5’ exonucleolytic cleavage.

[0204] In some embodiments, one or more of the synthetic nucleotide analogues described herein have increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. The one or more of the synthetic nucleotide analogues comprising 2’ -O-methyl, 2’-O-methoxyethyl (2’-O-MOE), 2’-O-aminopropyl, 2'-deoxy, 2’- deoxy-2'-fluoro, 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2’-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2' -O-dimethylaminoethyloxy ethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modified, LNA, ENA, PNA, HNA, morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, or 2’-fluoro N3-P5’-phosphoramidites have increased binding affinity toward their mRNA target relative to - 67 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTan equivalent natural polynucleic acid molecule. In some instances, a 2’-O-methyl modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2’ -O-methoxyethyl (2’-O-MOE) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2'-O-aminopropyl modified oligonucleotide molecule has increased binding affinity toward an mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, 2'-deoxy modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2’-deoxy-2'-fluoro modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2'-O-aminopropyl (2'-O-AP) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2'-O-dimethylaminoethyl (2'-O-DMAOE) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2’-O-dimethylaminopropyl (2'-O-DMAP) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2’-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a 2'-O-N-methylacetamido (2'-O-NMA) modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, an LNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, an ENA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a PNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, an HNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a morpholino modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a methylphosphonate nucleotides modified oligonucleotide - 68 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmolecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, a thiolphosphonate nucleotides modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some instances, an oligonucleotide molecule comprising 2’ -fluoro N3-P5’-phosphoramidites has increased binding affinity toward an mRNA target relative to an equivalent natural polynucleic acid molecule. In some cases, the increased affinity is illustrated with a lower Kd, a higher melt temperature (Tm), or a combination thereof.

[0205] In some embodiments, an oligonucleotide molecule described herein is a chirally pure (or stereo pure) polynucleic acid molecule, or a polynucleic acid molecule comprising a single enantiomer. In some instances, the oligonucleotide molecule comprises L-nucleotide. In some instances, the oligonucleotide molecule comprises D-nucleotides. In some instance, an oligonucleotide molecule composition comprises less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or less of its mirror enantiomer. In some cases, an oligonucleotide molecule composition comprises less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or less of a racemic mixture.

[0206] In some embodiments, an oligonucleotide molecule described herein is further modified to include an aptamer conjugating moiety. In some instances, the aptamer conjugating moiety is a DNA aptamer conjugating moiety. In some instances, the aptamer conjugating moiety is Alphamer, which comprises an aptamer portion that recognizes a specific cell-surface target and a portion that presents a specific epitope for attaching to circulating antibodies.

[0207] In additional embodiments, an oligonucleotide molecule described herein is modified to increase its stability. In some embodiment, the oligonucleotide molecule is RNA (e.g., siRNA). In some instances, the oligonucleotide molecule is modified by one or more of the modifications described above to increase its stability. In some cases, the oligonucleotide molecule is modified at the 2’ hydroxyl position, such as by 2’-O-methyl, 2’-O-methoxyethyl (2’-O-MOE), 2’-O-aminopropyl, 2'-deoxy, 2’-deoxy-2'-fluoro, 2'-O-aminopropyl (2'-O-AP), 2'- O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2’-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O-N-methylacetamido (2'-O-NMA) modification or by a locked or bridged ribose conformation (e.g., LNA or ENA). In some cases, the oligonucleotide molecule is modified by 2’-O-methyl and / or 2’-O-methoxyethyl ribose. In some cases, the oligonucleotide molecule also includes morpholines, PNAs, HNA, methylphosphonate nucleotides, thiolphosphonate nucleotides, and / or 2’-fluoro N3-P5’- - 69 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTphosphoramidites to increase its stability. In some instances, the oligonucleotide molecule is a chirally pure (or stereo pure) oligonucleotide molecule. In some instances, the chirally pure (or stereo pure) oligonucleotide molecule is modified to increase its stability. Suitable modifications to the RNA to increase stability for delivery will be apparent to the skilled person.

[0208] In some embodiments, the oligonucleotide molecule comprises 2’ modifications. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 3, 7, 8, 9, 12, and 17 from the 5’ end of the sense strand are not modified with a 2’-O-methyl modification. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 3, 7, 8, 9, 12, and 17 from the 5' end of the sense strand are modified with a 2’ -fluoro modification. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 2 and 14 from the 5’ end of the antisense strand are not modified with a 2’ -O-methyl modification. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 2 and 14 from the 5’ end of the antisense strand are modified with a 2’-fluoro modification. In some embodiments, any of the nucleotides may further comprise a 5’-phosphorothioate group modification. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 1 and 2 from the 5’ end of the sense strand are modified with a 5’-phosphorothioate group modification. In some embodiments, the nucleotides of the oligonucleotide molecule at positions 1, 2, 20, and 21 from the 5’ end of the antisense strand are modified with a 5’-phosphorothioate group modification. In some embodiments, the 5’ end of the sense or antisense strand of the oligonucleotide molecule may further comprise a vinyl phosphonate modification. In some embodiments, the nucleotide of the oligonucleotide molecule at position 1 from the 5’ end of the antisense strand is modified with a vinyl phosphonate modification.

[0209] In some instances, the oligonucleotide molecule is a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. In some instances, the oligonucleotide molecule is assembled from two separate polynucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (e.g., each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double stranded - 70 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTstructure, for example wherein the double stranded region is about 19, 20, 21, 22, 23, or more base pairs): the antisense strand comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. Alternatively, the oligonucleotide molecule is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the oligonucleotide molecule are linked by means of a nucleic acid-based or non-nucleic acidbased linker! s).

[0210] In some cases, the oligonucleotide molecule is a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises a nucleic acid (e.g., nucleobase) sequence that is complementary to a nucleic acid sequence in a separate target nucleic acid molecule or a portion thereof and the sense region comprises a nucleic acid (e.g., nucleobase) sequence corresponding to the target nucleic acid sequence or a portion thereof. In other cases, the oligonucleotide molecule is a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises a nucleic acid (e.g., nucleobase) sequence that is complementary to a nucleic acid sequence in a target nucleic acid molecule or a portion thereof and the sense region comprises a nucleic acid (e.g., nucleobase) sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide is processed either in vivo or in vitro to generate an active oligonucleotide molecule capable of mediating RNAi. In additional cases, the oligonucleotide molecule also comprises a single-stranded polynucleotide comprising a nucleic acid (e.g., nucleobase) sequence complementary to a nucleic acid sequence in a target nucleic acid molecule or a portion thereof (for example, where such oligonucleotide molecule does not require the presence within the oligonucleotide molecule of a nucleic acid sequence corresponding to the target nucleic acid sequence or a portion thereol), wherein the single stranded polynucleotide further comprises a terminal phosphate group, such as a 5'-phosphate, or 5', 3 '-diphosphate.

[0211] In some instances, an asymmetric hairpin is a linear oligonucleotide molecule comprising an antisense region, a loop portion that comprises nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complimentary nucleotides to base pair with the antisense region and form a duplex with loop. For example, an asymmetric hairpin oligonucleotide - 71 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmolecule comprises an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g., about 16 to about 25 nucleotides) and a loop region comprising about 4 to about 8 nucleotides, and a sense region having about 3 to about 18 nucleotides that are complementary to the antisense region. In some cases, the asymmetric hairpin oligonucleotide molecule also comprises a 5 '-terminal phosphate group that is chemically modified. In additional cases, the loop portion of the asymmetric hairpin oligonucleotide molecule comprises nucleotides, non-nucleotides, linker molecules, or conjugate molecules.

[0212] In some embodiments, an asymmetric duplex is an oligonucleotide molecule having two separate strands comprising a sense region and an antisense region, wherein the sense region comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complimentary nucleotides to base pair with the antisense region and form a duplex. For example, an asymmetric duplex oligonucleotide molecule comprises an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g., about 6 to about 25 nucleotides) and a sense region having about 3 to about 19 nucleotides that are complementary to the antisense region. In some embodiments, the antisense strand is comprised essentially of 21 nucleotides. In some embodiments, the sense strand is comprised essentially of 19 nucleotides. In some embodiments, the Sense strand is comprised essentially of 20 nucleotides.

[0213] In some cases, a universal base refers to nucleotide base analogs that form base pairs with each of the natural DNA / RNA bases with little discrimination between them. Non-limiting examples of universal bases include C-phenyl, C-naphthyl and other aromatic derivatives, inosine, azole carboxamides, and nitroazole derivatives such as 3 -nitropyrrole, 4-nitroindole, 5-nitroindole, and 6-nitroindole, as known in the art.

[0214] In some embodiments, the dsRNA agents are 5’ phosphorylated or include a phosphoryl analog at the 5’ terminus. 5’-phosphate modifications include those which are compatible with RISC mediated gene silencing. Suitable modifications include: 5’-monophosphate (HC>2(O)P— O-5'); 5 '-diphosphate ((HO)2(O)P— O— P(HO)(O)— O-5'); 5'-triphosphate ((HO)2(O)P— O— (HO)(O)P— O— P(HO)(O)— O-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-O-5'-(HO)(O)P-O— (HO)(O)P— O-P(HO)(O)-O-5'); 5'-adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (N-O-5'-(HO)(O)P— O— (HO)(O)P— O— P(HO)(O)— O-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)P— O-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)P— 0-5'), 5'-phosphorothiolate ((HO)2(O)P— S-5'); phosphorodithioate [-O2PS2— ]; phosphonate [- PO(OH)2-]; phosphoramidate [-O=P(OH)2— ]; mesyl phosphoramidate- 72 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT(CH3)(SO2)(N)P(O)2— 0-5'); any additional combination of oxygen / sulfur replaced monophosphate, diphosphate and triphosphates (e.g., 5 ’-alpha-thiotriphosphate, 5’-gamma-thiotriphosphate, etc.), 5’-phosphoramidates ((HO)2(O)P — NH-5’, (H0)(NH2)(0)P — 0-5’), 5’-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)— 0-5'-, 5'-alkenylphosphonates (i.e. vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5'-alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g., RP(0H)(0)-0-5'-). In some embodiments, the modification can be placed in the antisense strand of a dsRNA agent.

[0215] Other modifications and patterns of modifications can be found in, for example, U. S. Patent No. 10,233,448, which is hereby incorporated by reference. Other modifications and patterns of modifications can be found in, for example, Anderson et al., Nucleic Acids Research, 2021, 49(16): 9026-9041, which is hereby incorporated by reference. Other modifications and patterns of modifications can be found in, for example, International Patent Publication No. W02021 / 030778, which is hereby incorporated by reference. Other modifications and patterns of modifications can be found in, for example, International Patent Publication No. W02021 / 030763, which is hereby incorporated by reference.

[0216] In some embodiments, the sequence of the oligonucleotide molecule is at least 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 99.5% complementary to a target sequence of IFIH1. In some embodiments, the target sequence of IFIH1 is a nucleic acid sequence of about 10-50 base pair length, about 15-50 base pair length, 15-40 base pair length, 15-30 base pair length, or 15-25 base pair length sequences in IFIH1, in which the first nucleotide of the target sequence starts at any nucleotide in IFIH1 mRNA transcript in the coding region, or in the 5' or 3 '-untranslated region (UTR). For example, the first nucleotide of the target sequence can be selected so that it starts at the nucleic acid location (nal, number starting from the 5'-end of the full length of IFIH1 mRNA, e.g., the 5'-end first nucleotide is nal 1) 1, nal 2, nal 3, nal 4, nal 5, nal 6, nal 7, nal 8, nal 9, nal 10, nal 11, nal 12, nal 13, nal 14, nal 15, nal 15, nal 16, nal 17, or any other nucleic acid location in the coding or noncoding regions (5'- or 3 '-untranslated region) of IFIH1 mRNA. In some embodiments, the first nucleotide of the target sequence can be selected so that it starts at a location within, or between, nal 10- nal 15, nal 10- nal 20, nal 50- nal 60, nal 55-nal 65, nal 75- nal 85, nal 95- nal 105, nal 135- nal 145, nal 155- nal 165, nal 225- nal 235, nal 265- nal 275, nal 275- nal 245, nal 245- nal 255. nal 285- nal 335, nal 335- nal 345, nal 385- nal 395, nal 515- nal 525, nal 665- nal 675, nal 675- nal 685, nal 695- nal 705, nal 705-nal 715, nal 875- nal 885, nal 885- nal 895, nal 895- nal 905, nal 1035- nal 1045, nal 1045- - 73 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTnal 1055, nal 1125- nal 1135, nal 1135- nal 1145, nal 1145- nal 1155. nal 1155- nal 1165, nal 1125- nal 1135, nal 1155- nal 1165, nal 1225- nal 1235, nal 1235- nal 1245, nal 1275- nal 1245, nal 1245- nal 1255, nal 1265- nal 1275, nal 1125- nal 1135, nal 1155- nal 1165, nal 1225- nal 1235, nal 1235- nal 1245, nal 1275- nal 1245, nal 1245- nal 1255, nal 1265- nal 1275, nal 1275- nal 1285, nal 1335- nal 1345, nal 1345- nal 1355, nal 1525- nal 1535, nal 1535- nal 1545, nal 1605- nal 1615, nal 1615-C.1625, nal 1625- nal 1635, nal 1635-1735, nal 1735-1835, nal 1835-1935, nal. 1836-1856, nal 1935-2000, nal 2000 -2100, nal 2100 -2200. nal 2200 -2260, nal 2260 -2400, nal 2400 -2500, nal 2500 -2600, nal 2600 -2700, nal 2700 -2800, nal 2800 -2500, nal 2500 -2600, nal 2600 -2700, nal 2700 -2800, nal 2800 -2860, etc.

[0217] In some embodiments, the sequence of IFIH1 mRNA is provided as NCBI Reference Sequence: NM_022168.4 Homo sapiens interferon induced with helicase C domain 1 (IFIH1), mRNA:CAAACTCTGTAAGAACTGCCTGACAGAAAGCTGGACTCAAAGCTCCTACCCGAGT GTGCAGCAGGATCGCCCCGGTCCGGGACCCCAGGCGCACACCGCAGAGTCCAAAG TGCCGCGCCTGCCGGCCGCACCTGCCTGCCGCGGCCCCGCGCGCCGCCCCGCTGC CCACCTGCCCGCCTGCCCACCTGCCCAGGTGCGAGTGCAGCCCCGCGCGCCGGCC TGAGAGCCCTGTGGACAACCTCGTCATTGTCAGGCACAGAGCGGTAGACCCTGCT TCTCTAAGTGGGCAGCGGACAGCGGCACGCACATTTCACCTGTCCCGCAGACAAC AGCACCATCTGCTTGGGAGAACCCTCTCCCTTCTCTGAGAAAGAAAGATGTCGAA TGGGTATTCCACAGACGAGAATTTCCGCTATCTCATCTCGTGCTTCAGGGCCAGG GTGAAAATGTACATCCAGGTGGAGCCTGTGCTGGACTACCTGACCTTTCTGCCTG CAGAGGTGAAGGAGCAGATTCAGAGGACAGTCGCCACCTCCGGGAACATGCAGGC AGTTGAACTGCTGCTGAGCACCTTGGAGAAGGGAGTCTGGCACCTTGGTTGGACT CGGGAATTCGTGGAGGCCCTCCGGAGAACCGGCAGCCCTCTGGCCGCCCGCTACA TGAACCCTGAGCTCACGGACTTGCCCTCTCCATCGTTTGAGAACGCTCATGATGA ATATCTCCAACTGCTGAACCTCCTTCAGCCCACTCTGGTGGACAAGCTTCTAGTT AGAGACGTCTTGGATAAGTGCATGGAGGAGGAACTGTTGACAATTGAAGACAGAA ACCGGATTGCTGCTGCAGAAAACAATGGAAATGAATCAGGTGTAAGAGAGCTACT AAAAAGGATTGTGCAGAAAGAAAACTGGTTCTCTGCATTTCTGAATGTTCTTCGT CAAACAGGAAACAATGAACTTGTCCAAGAGTTAACAGGCTCTGATTGCTCAGAAA GCAATGCAGAGATTGAGAATTTATCACAAGTTGATGGTCCTCAAGTGGAAGAGCA ACTTCTTTCAACCACAGTTCAGCCAAATCTGGAGAAGGAGGTCTGGGGCATGGAG AATAACTCATCAGAATCATCTTTTGCAGATTCTTCTGTAGTTTCAGAATCAGACA CAAGTTTGGCAGAAGGAAGTGTCAGCTGCTTAGATGAAAGTCTTGGACATAACAG- 74 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTCAACATGGGCAGTGATTCAGGCACCATGGGAAGTGATTCAGATGAAGAGAATGTG GCAGCAAGAGCATCCCCGGAGCCAGAACTCCAGCTCAGGCCTTACCAAATGGAAG TTGCCCAGCCAGCCTTGGAAGGGAAGAATATCATCATCTGCCTCCCTACAGGGAG TGGAAAAACCAGAGTGGCTGTTTACATTGCCAAGGATCACTTAGACAAGAAGAAA AAAGCATCTGAGCCTGGAAAAGTTATAGTTCTTGTCAATAAGGTACTGCTAGTTG AACAGCTCTTCCGCAAGGAGTTCCAACCATTTTTGAAGAAATGGTATCGTGTTAT TGGATTAAGTGGTGATACCCAACTGAAAATATCATTTCCAGAAGTTGTCAAGTCC TGTGATATTATTATCAGTACAGCTCAAATCCTTGAAAACTCCCTCTTAAACTTGG AAAATGGAGAAGATGCTGGTGTTCAATTGTCAGACTTTTCCCTCATTATCATTGA TGAATGTCATCACACCAACAAAGAAGCAGTGTATAATAACATCATGAGGCATTAT T T GAT G C AGAAGT T G AAAAAC AAT AG AC T C AAGAAAG AAAAC AAAC C AGT GATT C CCCTTCCTCAGATACTGGGACTAACAGCTTCACCTGGTGTTGGAGGGGCCACGAA GCAAGCCAAAGCTGAAGAACACATTTTAAAACTATGTGCCAATCTTGATGCATTT ACTATTAAAACTGTTAAAGAAAACCTTGATCAACTGAAAAACCAAATACAGGAGC CATGCAAGAAGTTTGCCATTGCAGATGCAACCAGAGAAGATCCATTTAAAGAGAA ACTTCTAGAAATAATGACAAGGATTCAAACTTATTGTCAAATGAGTCCAATGTCA GATTTTGGAACTCAACCCTATGAACAATGGGCCATTCAAATGGAAAAAAAAGCTG C AAAAG AAGG AAAT C GC AAAGAAC GT GT T T GT GC AGAAC AT T T GAG GAAG T ACAA TGAGGCCCTACAAATTAATGACACAATTCGAATGATAGATGCGTATACTCATCTT GAAACTTTCTATAATGAAGAGAAAGATAAGAAGTTTGCAGTCATAGAAGATGATA GTGATGAGGGTGGTGATGATGAGTATTGTGATGGTGATGAAGATGAGGATGATTT AAAG AAAC C T T T G AAAC T G G AT G AAAC AG AT AG AT TTCTCATGACTTTATTTTTT G AAAAC AAT AAAAT G T T G AAAAG G C T GG C T G AAAAC C C AG AAT AT G AAAAT G AAA AGCTGACCAAATTAAGAAATACCATAATGGAGCAATATACTAGGACTGAGGAATC AGCACGAGGAATAATCTTTACAAAAACACGACAGAGTGCATATGCGCTTTCCCAG TGGATTACTGAAAATGAAAAATTTGCTGAAGTAGGAGTCAAAGCCCACCATCTGA TTGGAGCTGGACACAGCAGTGAGTT C AAAC CCATGACACAGAAT G AAC AAAAAG A AGTCATTAGTAAATTTCGCACTGGAAAAATAAATCTGCTTATCGCTACCACAGTG GCAGAAGAAGGTCTGGATATTAAAGAATGTAACATTGTTATCCGTTATGGTCTCG TCACCAATGAAATAGCCATGGTCCAGGCCCGTGGTCGAGCCAGAGCTGATGAGAG CACCTACGTCCTGGTTGCTCACAGTGGTTCAGGAGTTATCGAACATGAGACAGTT AATGATTTCCGAGAGAAGATGATGTATAAAGCTATACATTGTGTTCAAAATATGA AACCAGAGGAGTATGCTCATAAGATTTTGGAATTACAGATGCAAAGTATAATGGA AAAGAAAATG AAAAC CAAGAGAAATATT GCCAAGCAT TACAAGAAT AACC CATCA- 75 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTCTAATAACTTTCCTTTGCAAAAACTGCAGTGTGCTAGCCTGTTCTGGGGAAGATA T C CAT G T AAT T GAGAAAAT GC AT C AC GT C AAT AT GAC C C C AGAAT T C AAG GAAC T TTACATTGTAAGAGAAAACAAAGCACTGCAAAAGAAGTGTGCCGACTATCAAATA AATGGTGAAATCATCTGCAAATGTGGCCAGGCTTGGGGAACAATGATGGTGCACA AAGGCTTAGATTTGCCTTGTCTCAAAATAAGGAATTTTGTAGTGGTTTTCAAAAA TAATTCAACAAAGAAACAATACAAAAAGTGGGTAGAATTACCTATCACATTTCCC AATCTTGACTATTCAGAATGCTGTTTATTTAGTGATGAGGATTAGCACTTGATTG AAG AT T C T T T T AAAAT AC T AT C AG T T AAAC AT TTAATATGATTATGATTAATGTA TTCATTATGCTACAGAACTGACATAAGAATCAATAAAATGATTGTTTTACTCTGC ATTGAA (SEQ ID NO: 46).

[0218] In some embodiments, the sequence of IFIH1 mRNA is provided as Ensembl Genome Browser Transcript: ENST00000648433. I (IFIH1-203), Homo sapiens interferon induced with helicase C domain 1:GCGCGCCGGCCTGAGAGCCCTGTGGACAACCTCGTCATTGTCAGGCACAGAGCGG TAGACCCTGCTTCTCTAAGTGGGCAGCGGACAGCGGCACGCACATTTCACCTGTC CCGCAGACAACAGCACCATCTGCTTGGGAGAACCCTCTCCCTTCTCTGAGAAAGA AAGATGTCGAATGGGTATTCCACAGACGAGAATTTCCGCTATCTCATCTCGTGCT TCAGGGCCAGGGTGAAAATGTACATCCAGGTGGAGCCTGTGCTGGACTACCTGAC CTTTCTGCCTGCAGAGGTGAAGGAGCAGATTCAGAGGACAGTCGCCACCTCCGGG AACATGCAGGCAGTTGAACTGCTGCTGAGCACCTTGGAGAAGGGAGTCTGGCACC TTGGTTGGACTCGGGAATTCGTGGAGGCCCTCCGGAGAACCGGCAGCCCTCTGGC CGCCCGCTACATGAACCCTGAGCTCACGGACTTGCCCTCTCCATCGTTTGAGAAC GCTCATGATGAATATCTCCAACTGCTGAACCTCCTTCAGCCCACTCTGGTGGACA AGCTTCTAGTTAGAGACGTCTTGGATAAGTGCATGGAGGAGGAACTGTTGACAAT TGAAGACAGAAACCGGATTGCTGCTGCAGAAAACAATGGAAATGAATCAGGTGTA AGAGAGCTACTAAAAAGGATTGTGCAGAAAGAAAACTGGTTCTCTGCATTTCTGA ATGTTCTTCGTCAAACAGGAAACAATGAACTTGTCCAAGAGTTAACAGGCTCTGA TTGCTCAGAAAGCAATGCAGAGATTGAGAATTTATCACAAGTTGATGGTCCTCAA GTGGAAGAGCAACTTCTTTCAACCACAGTTCAGCCAAATCTGGAGAAGGAGGTCT GGGGCATGGAGAATAACTCATCAGAATCATCTTTTGCAGATTCTTCTGTAGTTTC AGAATCAGACACAAGTTTGGCAGAAGGAAGTGTCAGCTGCTTAGATGAAAGTCTT GGACATAACAGCAACATGGGCAGTGATTCAGGCACCATGGGAAGTGATTCAGATG AAGAGAATGTGGCAGCAAGAGCATCCCCGGAGCCAGAACTCCAGCTCAGGCCTTA CCAAATGGAAGTTGCCCAGCCAGCCTTGGAAGGGAAGAATATCATCATCTGCCTC- 76 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTCCTACAGGGAGTGGAAAAACCAGAGTGGCTGTTTACATTGCCAAGGATCACTTAG ACAAGAAGAAAAAAGCATCTGAGCCTGGAAAAGTTATAGTTCTTGTCAATAAGGT ACTGCTAGTTGAACAGCTCTTCCGCAAGGAGTTCCAACCATTTTTGAAGAAATGG TATCGTGTTATTGGATTAAGTGGTGATACCCAACTGAAAATATCATTTCCAGAAG TTGTCAAGTCCTGTGATATTATTATCAGTACAGCTCAAATCCTTGAAAACTCCCT CTTAAACTTGGAAAATGGAGAAGATGCTGGTGTTCAATTGTCAGACTTTTCCCTC ATTATCATTGATGAATGTCATCACACCAACAAAGAAGCAGTGTATAATAACATCA TGAGGCATTATTTGATGCAGAAGTTGAAAAACAATAGACTCAAGAAAGAAAACAA ACCAGTGATTCCCCTTCCTCAGATACTGGGACTAACAGCTTCACCTGGTGTTGGA GGGGCCACGAAGCAAGCCAAAGCTGAAGAACACATTTTAAAAGATCCATTTAAAG AGAAACTTCTAGAAATAATGACAAGGATTCAAACTTATTGTCAAATGAGTCCAAT GTCAGATTTTGGAACTCAACCCTATGAACAATGGGCCATTCAAATGGAAAAAAAA GCTGCAAAAGAAGGAAATCGCAAAGAACGTGTTTGTGCAGAACATTTGAGGAAGT ACAATGAGGCCCTACAAATTAATGACACAATTCGAATGATAGATGCGTATACTCA TCTTGAAACTTTCTATAATGAAGAGAAAGATAAGAAGTTTGCAGTCATAGAAGAT GATAGTGATGAGGGTGGTGATGATGAGTATTGTGATGGTGATGAAGATGAGGATG ATT T AAAG AAAC C T T T G AAAC T G G AT G AAAC AG AT AG AT TTCTCATGACTTTATT T T T T GAAAAC AAT AAAATG T T GAAAAGG C T GG C T GAAAACC C AGAAT ATG AAAAT GAAAAGCTGACCAAATTAAGAAATACCATAATGGAGCAATATACTAGGACTGAGG AATCAGCACGAGGAATAATCTTTACAAAAACACGACAGAGTGCATATGCGCTTTC CCAGTGGATTACTGAAAATGAAAAATTTGCTGAAGTAGGAGTCAAAGCCCACCAT C T GAT T GGAG C T GGAC AC AGC AGT GAGT T C AAAC C C AT GAC AC AGAAT GAAC AAA AAGAAGTCATTAGTAAATTTCGCACTGGAAAAATAAATCTGCTTATCGCTACCAC AGTGGCAGAAGAAGGTCTGGATATTAAAGAATGTAACATTGTTATCCGTTATGGT CTCGTCACCAATGAAATAGCCATGGTCCAGGCCCGTGGTCGAGCCAGAGCTGATG AGAGCACCTACGTCCTGGTTGCTCACAGTGGTTCAGGAGTTATCGAACATGAGAC AGTTAATGATTTCCGAGAGAAGATGATGTATAAAGCTATACATTGTGTTCAAAAT ATGAAACCAGAGGAGTATGCTCATAAGATTTTGGAATTACAGATGCAAAGTATAA T GGAAAAGAAAAT GAAAAC CAAGAGAAATATT GCC AAGCAT TAC AAGAAT AACCC ATCACTAATAACTTTCCTTTGCAAAAACTGCAGTGTGCTAGCCTGTTCTGGGGAA GATATCCATGTAATTGAGAAAATGCATCACGTCAATATGACCCCAGAATTCAAGG AACTTTACATTGTAAGAGAAAACAAAGCACTGCAAAAGAAGTGTGCCGACTATCA AATAAATGGTGAAATCATCTGCAAATGTGGCCAGGCTTGGGGAACAATGATGGTG CACAAAGGCTTAGATTTGCCTTGTCTCAAAATAAGGAATTTTGTAGTGGTTTTCA- 77 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTAAAATAATTCAACAAAGAAACAATACAAAAAGTGGGTAGAATTACCTATCACATT TCCCAATCTTGACTATTCAGAATGCTGTTTATTTAGTGATGAGGATTAGCACTTG ATTGAAGATTCTTTTAAAATACTATCAGTTAAACATTTAATATGATTATGATTAA TGTATTCATTATGCTACAGAACTGACATAAGAATCAATAAAATG (SEQ ID NO: 1955).

[0219] In some embodiments, the sequence of IFIH1 mRNA is provided as Ensembl Genome Browser Transcript: ENST00000679938.1 (IFIH1-207), Homo sapiens interferon induced with helicase C domain 1:AGGTGGAGCCTGTGCTGGACTACCTGACCTTTCTGCCTGCAGAGGTGAAGGAGCA GATTCAGAGGACAGTCGCCACCTCCGGGAACATGCAGGCAGTTGAACTGCTGCTG AGCACCTTGGAGAAGGGAGTCTGGCACCTTGGTTGGACTCGGGAATTCGTGGAGG CCCTCCGGAGAACCGGCAGCCCTCTGGCCGCCCGCTACATGAACCCTGAGCTCAC GGACTTGCCCTCTCCATCGTTTGAGAACGCTCATGATGAATATCTCCAACTGCTG AACCTCCTTCAGCCCACTCTGGTGGACAAGCTTCTAGTTAGAGACGTCTTGGATA AGTGCATGGAGGAGGAACTGTTGACAATTGAAGACAGAAACCGGATTGCTGCTGC AGAAAACAATGGAAATGAATCAGGTGTAAGAGAGCTACTAAAAAGGATTGTGCAG AAAGAAAACTGGTTCTCTGCATTTCTGAATGTTCTTCGTCAAACAGGAAACAATG AACTTGTCCAAGAGTTAACAGGCTCTGATTGCTCAGAAAGCAATGCAGAATCAGA CACAAGTTTGGCAGAAGGAAGTGTCAGCTGCTTAGATGAAAGTCTTGGACATAAC AGCAACATGGGCAGTGATTCAGGCACCATGGGAAGTGATTCAGATGAAGAGAATG TGGCAGCAAGAGCATCCCCGGAGCCAGAACTCCAGCTCAGGCCTTACCAAATGGA AGTTGCCCAGCCAGCCTTGGAAGGGAAGAATATCATCATCTGCCTCCCTACAGGG AGTGGAAAAACCAGAGTGGCTGTTTACATTGCCAAGGATCACTTAGACAAGAAGA AAAAAGCATCTGAGCCTGGAAAAGTTATAGTTCTTGTCAATAAGGTACTGCTAGT TGAACAGCTCTTCCGCAAGGAGTTCCAACCATTTTTGAAGAAATGGTATCGTGTT ATTGGATTAAGTGGTGATACCCAACTGAAAATATCATTTCCAGAAGTTGTCAAGT CCTGTGATATTATTATCAGTACAGCTCAAATCCTTGAAAACTCCCTCTTAAACTT GGAAAATGGAGAAGATGCTGGTGTTCAATTGTCAGACTTTTCCCTCATTATCATT GATGAATGTCATCACACCAACAAAGAAGCAGTGTATAATAACATCATGAGGCATT ATTTGATGCAGAAGTTGAAAAACAATAGACTCAAGAAAGAAAACAAACCAGTGAT TCCCCTTCCTCAGATACTGGGACTAACAGCTTCACCTGGTGTTGGAGGGGCCACG AAGCAAGCCAAAGCTGAAGAACACATTTTAAAACTATGTGCCAATCTTGATGCAT T T AC T AT T AAAAC T G T T AAAG AAAAC CTTGATCAACT G AAAAAC C AAAT AC AG GA GCCATGCAAGAAGTTTGCCATTGCAGATGCAACCAGAGAAGATCCATTTAAAGAG- 78 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTAAACTTCTAGAAATAATGACAAGGATTCAAACTTATTGTCAAATGAGTCCAATGT CAGATTTTGGAACTCAACCCTATGAACAATGGGCCATT C AAAT G G AAAAAAAAG C TGCAAAAGAAGGAAATCGCAAAGAACGTGTTTGTGCAGAACATTTGAGGAAGTAC AATGAGGCCCTACAAATTAATGACACAATTCGAATGATAGATGCGTATACTCATC T T G AAA C T T T C T AT A AT G A AG AG A AAG A T AAG AAG T T T G C A G T C AT AG AA G AT G A TAGTGATGAGGGTGGTGATGATGAGTATTGTGATGGTGATGAAGATGAGGATGAT T T AAAG AAAC C T T T G AAAC T G G AT G AAAC AG AT AG AT TTCTCATGACTTTATTTT TTGAAAACAATAAAATGTTGAAAAGGCTGGCTGAAAACCCAGAATATGAAAATGA AAAGCTGACCAAATTAAGAAATACCATAATGGAGCAATATACTAGGACTGAGGAA TCAGCACGAGGAATAATCTTTACAAAAACACGACAGAGTGCATATGCGCTTTCCC AGTGGATTACTGAAAATGAAAAATTTGCTGAAGTAGGAGTCAAAGCCCACCATCT GATTGGAGCTGGACACAGCAGTGAGTTCAAACCCATGACACAGAATGAACAAAAA GAAGTCATTAGTAAATTTCGCACTGGAAAAATAAATCTGCTTATCGCTACCACAG TGGCAGAAGAAGGTCTGGATATTAAAGAATGTAACATTGTTATCCGTTATGGTCT CGTCACCAATGAAATAGCCATGGTCCAGGCCCGTGGTCGAGCCAGAGCTGATGAG AGCACCTACGTCCTGGTTGCTCACAGTGGTTCAGGAGTTATCGAACATGAGACAG TTAATGATTTCCGAGAGAAGATGATGTATAAAGCTATACATTGTGTTCAAAATAT GAAACCAGAGGAGTATGCTCATAAGATTTTGGAATTACAGATGCAAAGTATAATG G AAAAG AAAAT GAAAAC C AAGAGAAAT AT T GC C AAGC AT T AC AAGAAT AAC C CAT CACTAATAACTTTCCTTTGCAAAAACTGCAGTGTGCTAGCCTGTTCTGGGGAAGA TATCCATGTAATTGAGAAAATGCATCACGTCAATATGACCCCAGAATTCAAGGAA CTTTACATTGTAAGAGAAAACAAAGCACTGCAAAAGAAGTGTGCCGACTATCAAA TAAATGGTGAAATCATCTGCAAATGTGGCCAGGCTTGGGGAACAATGATGGTGCA CAAAGGCTTAGATTTGCCTTGTCTCAAAATAAGGAATTTTGTAGTGGTTTTCAAA AATAATTCAACAAAGAAACAATACAAAAAGTGGGTAGAATTACCTATCACATTTC CCAATCTTGACTATTCAGAATGCTGTTTATTTAGTGATGAGGATTAGCACTTGAT TGAAGATTCTTTTAAAATACTATCAGTTAAACATTTAATATGATTATGATTAATG TATTCATTATGCTACAGAACTGACATAAGAATCAATAAAATGATTGTTT (SEQ ID NO: 1956).

[0220] In some embodiments, the antisense strand of the dsRNA agent is 100% complementary to a target RNA to hybridize thereto, and inhibits expression of the target RNA through RNA interference. The target RNA can be any RNA expressed in a cell. In another embodiment, the cell is a tumor cell, a liver cell, a muscle cell, an immune cell, a heart cell, a cell of the central nervous system, or any other CD71 -positive cell, including- 79 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTparenchymal, stromal, progenitor, or immune cells, in which IFIH1 / MDA5 activity is associated with interferon signaling, inflammation, or disease. In some embodiments, the cell is a tumor cell, a liver cell, a muscle cell, an immune cell, a heart cell, or a cell of the central nervous system; or is selected from a pancreatic cell (including a pancreatic 0 cell), an endocrine cell, a vascular cell (including a vascular smooth muscle cell, endothelial cell, or pericyte), an epithelial cell, a stromal or mesenchymal cell, a fibroblast, a progenitor or stem cell, a hematopoietic cell, a neuronal or glial cell, a renal cell, a pulmonary cell, a gastrointestinal cell, a dermal or epidermal cell, an adipocyte or preadipocyte, a musculoskeletal cell, or any other CD71 -positive cell in which IFIH1 / MDA5 signaling contributes to a pathological interferon or inflammatory response. In another embodiment, the antisense strand of the dsRNA agent is at least 99%, at least 98%, at least 97%, at least 96%, 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, or at least 50% complementary to a target RNA. In some embodiments, the target RNA is IFIH1 RNA. In some embodiments, the siRNA molecule is an siRNA molecule that reduces mRNA expression of IFIH1. In some embodiments, the siRNA molecule is an siRNA molecule that reduces mRNA expression of IFIH1 and does not reduce expression of other RNAs by more than 50% in an assay described herein at a concentration of no more than 200 nm as described herein.

[0221] In some embodiments, the siRNA molecule is linked to a protein, such as an FN3 domain. The siRNA molecule can be linked to multiple FN3 domains that bind to the same target protein or different target proteins. In some embodiments, the siRNA molecule is linked to the FN3 domain via a linker. In some embodiments, the linker is attached to the sense strand of the siRNA molecule, and is used to facilitate the linkage of the sense strand to the FN3 domain.

[0222] In some embodiments, compositions are provided herein having a formula of (Xl)n-(X2)q-(X3)y-L-X4, wherein XI is a first FN3 domain, X2 is a second FN3 domain, X3 is a third FN3 domain or half-life extender molecule, Fis a linker, and X4 is a nucleic acid molecule, such as, but not limited to an siRNA molecule, wherein n, q, and y are each independently 0 or 1. In some embodiments, XI, X2, and X3 bind to different target proteins. In some embodiments, y is 0. In some embodiments, n is 1, q is 0, and y is 0. In some embodiments, n is 1, q is 1, and y is 0. In some embodiments, n is 1, q is 1, and y is 1. In some embodiments, X3 increases the half-life of the molecule as a whole as compared to a molecule without X3.- 80 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0223] In some embodiments, the half-life extender molecule is an FN3 domain that binds to albumin. Examples of such FN3 domains include, but are not limited to, those described in U. S. Patent Application Publication No. 2017 / 0348397 and U. S. Patent No. 9,156,887, which are hereby incorporated by reference in their entireties. The FN3 domains may incorporate other subunits, for example, via covalent interaction. In some embodiments, the FN3 domains further comprise a half-life extending moiety. Exemplary half-life extending moieties are albumin, albumin variants, albumin-binding proteins and / or domains, an aliphatic chain that binds to serum proteins, transferrin and fragments and analogues thereof, and Fc regions. Amino acid sequences of the human Fc regions are well known, and include IgGl, IgG2, IgG3, IgG4, IgM, IgA and IgE Fc regions. In some embodiments, the FN3 domains may incorporate a second FN3 domain that binds to a molecule that extends the half-life of the entire molecule, such as, but not limited to, any of the half-life extending moieties described herein. In some embodiments, the second FN3 domain binds to albumin, albumin variants, albumin-binding proteins and / or domains, and fragments and analogues thereof.

[0224] In some embodiments, compositions are provided herein having a formula of (X1)-(X2)-L-(X4), wherein XI is a first FN3 domain, X2 is a second FN3 domain, L is a linker, and X4 is a nucleic acid molecule. In some embodiments, X4 is an siRNA molecule. In some embodiments, XI is an FN3 domain that binds to CD71. In some embodiments, X2 is an FN3 domain that binds to CD71. In some embodiments XI and X2 do not bind to the same target protein. In some embodiments, XI and X2 bind to the same target protein. In some embodiments, XI and X2 bind to the same target protein, but at different binding sites on the protein. In some embodiments, XI and X2 bind to different epitopes of the same target protein. In some embodiments, XI and X2 are FN3 domains that bind to CD71.

[0225] In some embodiments, compositions are provided herein having a formula of C-(X1)n-(X2)q[L-X4]-(X3)y, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; X4 is an oligonucleotide molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1, are provided.

[0226] In some embodiments, compositions are provided herein having a formula of (X1)n-(X2)q[L-X4]-(X3)y-C, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; X4 is an oligonucleotide molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1, are provided.- 81 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0227] In some embodiments, compositions are provided herein having a formula of C-(Xl)n-(X2)q[L-X4]L-(X3)y, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; E is a linker; X4 is an oligonucleotide molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1, are provided.

[0228] In some embodiments, compositions are provided herein having a formula of (Xl)n-(X2)q[L-X4]L-(X3)y-C, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; E is a linker; X4 is an oligonucleotide molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1, are provided.

[0229] In some embodiments, compositions or complexes are provided having a formula of Ai-Bi, wherein Ai has a formula of C-Li-Xsand Bi has a formula of XAS-L2-F1, wherein:C is a polymer, such as PEG;Li and L2 are each, independently, a linker;Xs is a 5’ to 3’ oligonucleotide sense strand of a double stranded siRNA molecule; XAS is a 3’ to 5’ oligonucleotide antisense strand of a double stranded siRNA molecule;Fi is a polypeptide comprising at least one FN3 domain;wherein Xs and XAS form a double stranded oligonucleotide molecule to form the composition / complex.

[0230] In some embodiments, compositions or complexes are provided having a formula of A1-B1, wherein Ai has a formula of Xsand Bi has a formula of XAS-L2-F1.

[0231] In some embodiments, compositions or complexes are provided having a formula of A1-B1, wherein Ai has a formula of C-Li-Xsand Bi has a formula of XAS.

[0232] In some embodiments, the sense strand is a sense strand as provided for herein. In some embodiments, the antisense strand is an antisense strand as provided for herein. In some embodiments, the sense and antisense strand form a double stranded siRNA molecule that targets IFI16 In some embodiments, the double stranded oligonucleotide is about 16-25 nucleotides base pairs in length. In certain embodiments, C is optional.

[0233] In some embodiments, compositions or complexes are provided having a formula of A1-B1, wherein Ai has a formula of Fi-Li-Xsand Bi has a formula of XAS-L2-C, wherein:Fi is a polypeptide comprising at least one FN3 domain;- 82 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTLi and L2 are each, independently, a linker;C is a polymer, such as PEG:Xs is a 5’ to 3’ oligonucleotide sense strand of a double stranded siRNA molecule; XAS is a 3’ to 5’ oligonucleotide antisense strand of a double stranded siRNA molecule;wherein Xs and XAS form a double stranded oligonucleotide molecule to form the composition / complex. In certain embodiments, C is optional.

[0234] In some embodiments, compositions or complexes are provided having a formula of A1-B1, wherein Ai has a formula of Xsand Bi has a formula of XAS-L2-C.

[0235] In some embodiments, compositions or complexes are provided having a formula of A1-B1, wherein Ai has a formula of Fi-Li-Xs and Bi has a formula of XAS.

[0236] In some embodiments, Ai and Bi interact with each other through hydrogen bonding. In some embodiments, Ai and Bi interact with each other through Watson-Crick base pairing.

[0237] In some embodiments, compositions comprising a polymer (polymer moiety C, or just C) are provided herein. In some embodiments, C is a molecule that extends the half-life of the molecule. In some embodiments, C is a natural or synthetic polymer, consisting of long chains of branched or unbranched monomers, and / or cross-linked network of monomers in two or three dimensions In some instances, C includes a polysaccharide, lignin, rubber, or polyalkylene oxide (e.g., polyethylene glycol). In some instances, C includes, but is not limited to, alpha-, omega-dihydroxylpolyethyleneglycol, biodegradable lactone-based polymer, e.g. polyacrylic acid, polylactide acid (PLA), poly(glycolic acid) (PGA), polypropylene, polystyrene, polyolefin, polyamide, polycyanoacrylate, polyimide, polyethylenterephthalat (PET, PETG), polyethylene terephthalate (PETE), polytetramethylene glycol (PTG), or polyurethane as well as mixtures thereof. As used herein, a mixture refers to the use of different polymers within the same compound as well as in reference to block copolymers. In some cases, block copolymers are polymers wherein at least one section of a polymer is build up from monomers of another polymer. In some instances, C comprises polyalkylene oxide. In some instances, C comprises PEG. In some instances, C comprises polyethylene imide (PEI) or hydroxy ethyl starch (HES).

[0238] In some embodiments, C is a PEG moiety. In some embodiments, the PEG moiety is conjugated at the 5’ terminus of the oligonucleotide molecule while the binding moiety is conjugated at the 3’ terminus of the oligonucleotide molecule. In some embodiments, the PEG moiety is conjugated at the 3’ terminus of the oligonucleotide - 83 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTmolecule while the binding moiety is conjugated at the 5’ terminus of the oligonucleotide molecule. In some embodiments, the PEG moiety is conjugated to an internal site of the oligonucleotide molecule. In some embodiments, the PEG moiety, the binding moiety, or a combination thereof, are conjugated to an internal site of the oligonucleotide molecule. In some embodiments, the conjugation is a direct conjugation. In some embodiments, the conjugation is via native ligation.

[0239] In some embodiments, the polyalkylene oxide (e.g., PEG) is a polydisperse or monodisperse compound. In some embodiments, polydisperse material comprises disperse distribution of different molecular weight of the material, characterized by mean weight (weight average) size and dispersity. In some embodiments, the monodisperse PEG comprises one size of molecules. In some embodiments, C is polydisperse or monodisperse polyalkylene oxide (e.g., PEG) and the indicated molecular weight represents an average of the molecular weight of the polyalkylene oxide, e.g., PEG, molecules.

[0240] In some embodiments, the molecular weight of the poly alkylene oxide (e.g., PEG) is about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4600, 4750, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 10,000, 12,000, 20,000, 35,000, 40,000, 50,000, 60,000, or 100,000 Da.

[0241] In some embodiments, C is poly alkylene oxide (e.g., PEG) and has a molecular weight of about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4600, 4750, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 10,000, 12,000, 20,000, 35,000, 40,000, 50,000, 60,000, or 100,000 Da. In some embodiments, C is PEG and has a molecular weight of about 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4600, 4750, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 10,000, 12,000, 20,000, 35,000, 40,000, 50,000, 60,000, or 100,000 Da. In some embodiments, the molecular weight of C is about 200 Da. In some embodiments, the molecular weight of C is about 300 Da. In some embodiments, the molecular weight of C is about 400 Da. In some embodiments, the molecular weight of C is about 500 Da. In some embodiments, the molecular weight of C is about 600 Da. In some embodiments, the molecular weight of C is about 700 Da. In some embodiments, the molecular weight of C is about 800 Da. In some embodiments, the molecular weight of C is about 900 Da. In some embodiments, the molecular weight of C is - 84 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTabout 1000 Da. In some embodiments, the molecular weight of C is about 1100 Da. In some embodiments, the molecular weight of C is about 1200 Da. In some embodiments, the molecular weight of C is about 1300 Da. In some embodiments, the molecular weight of C is about 1400 Da. In some embodiments, the molecular weight of C is about 1450 Da. In some embodiments, the molecular weight of C is about 1500 Da. In some embodiments, the molecular weight of C is about 1600 Da. In some embodiments, the molecular weight of C is about 1700 Da. In some embodiments, the molecular weight of C is about 1800 Da. In some embodiments, the molecular weight of C is about 1900 Da. In some embodiments, the molecular weight of C is about 2000 Da. In some embodiments, the molecular weight of C is about 2100 Da. In some embodiments, the molecular weight of C is about 2200 Da. In some embodiments, the molecular weight of C is about 2300 Da. In some embodiments, the molecular weight of C is about 2400 Da. In some embodiments, the molecular weight of C is about 2500 Da. In some embodiments, the molecular weight of C is about 2600 Da. In some embodiments, the molecular weight of C is about 2700 Da. In some embodiments, the molecular weight of C is about 2800 Da. In some embodiments, the molecular weight of C is about 2900 Da. In some embodiments, the molecular weight of C is about 3000 Da. In some embodiments, the molecular weight of C is about 3250 Da. In some embodiments, the molecular weight of C is about 3350 Da. In some embodiments, the molecular weight of C is about 3500 Da. In some embodiments, the molecular weight of C is about 3750 Da. In some embodiments, the molecular weight of C is about 4000 Da. In some embodiments, the molecular weight of C is about 4250 Da. In some embodiments, the molecular weight of C is about 4500 Da. In some embodiments, the molecular weight of C is about 4600 Da. In some embodiments, the molecular weight of C is about 4750 Da. In some embodiments, the molecular weight of C is about 5000 Da. In some embodiments, the molecular weight of C is about 5500 Da. In some embodiments, the molecular weight of C is about 6000 Da. In some embodiments, the molecular weight of C is about 6500 Da. In some embodiments, the molecular weight of C is about 7000 Da. In some embodiments, the molecular weight of C is about 7500 Da. In some embodiments, the molecular weight of C is about 8000 Da. In some embodiments, the molecular weight of C is about 10,000 Da. In some embodiments, the molecular weight of C is about 12,000 Da. In some embodiments, the molecular weight of C is about 20,000 Da. In some embodiments, the molecular weight of C is about 35,000 Da. In some embodiments, the molecular weight of C is about 40,000 Da. In some embodiments, the molecular weight of C is about 50,000 Da. In some embodiments, the molecular weight of C is about 60,000 Da. In some embodiments, the molecular weight of C is about 100,000 Da.- 85 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT

[0242] In some embodiments, the polyalkylene oxide (e.g., PEG) is a discrete PEG, in which the discrete PEG is a polymeric PEG comprising more than one repeating ethylene oxide units. In some embodiments, a discrete PEG (dPEG) comprises from 2 to 60, from 2 to 50, or from 2 to 48 repeating ethylene oxide units. In some embodiments, a dPEG comprises about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 2 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 3 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 4 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 5 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 6 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 7 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 8 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 9 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 10 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 11 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 12 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 13 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 14 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 15 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 16 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 17 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 18 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 19 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 20 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 22 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 24 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 26 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 28 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 30 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 35 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 40 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 42 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises about 48 or more repeating ethylene oxide units. In some embodiments, a dPEG comprises - 86 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTabout 50 or more repeating ethylene oxide units. In some cases, a dPEG is synthesized as a single molecular weight compound from pure (e.g., about 95%, 98%, 99%, or 99.5%) starting material in a step-wise fashion. In some cases, a dPEG has a specific molecular weight, rather than an average molecular weight. In some cases, a dPEG described herein is a dPEG from Quanta Biodesign, Ltd..

[0243] In some embodiments, C is an albumin binding domain polypeptide. In some embodiments, the albumin binding domain specifically binds to serum albumin, e.g., human serum albumin (HSA), to prolong the half-life of the domain or of another therapeutic to which the albumin-binding domain is associated with or linked to. In some embodiments, the human serum albumin-binding domain comprises an initiator methionine (Met) linked to the N-terminus of the molecule. In some embodiments, the human serum albumin-binding domain comprises a cysteine (Cys) linked to a C-terminus or the N-terminus of the domain. The addition of the N-terminal Met and / or the C-terminal Cys may facilitate expression and / or conjugation to another molecule, which can be another half-life extending molecule, such as PEG, a Fc region, and the like.

[0244] In some embodiments, the albumin binding domain comprises the amino acid sequence of any of SEQ ID NO: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, provided in Table 1.Table 1: Albumin-binding DomainsSEQ ID Amino Acid SequenceNO:MLPAPKNLVASRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS5ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS6ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFAIAYWEPGIGGEAIWLRVPGS7ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNISYWEPGIGGEAIWLRVPGS8ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYAEPGIGGEAIWLRVPGS9 RSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEAGIGGEAIWLRVPGS10ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPAIGGEAIWLRVPGS11 ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGAGGEAIWLRVPGS12ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGI AGEAIWLRVPGS13 ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIALRVPGS14ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT- 87 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTTable 1: Albumin-binding DomainsSEQ ID Amino Acid SequenceNO:MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLAVPGS15ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS16ERSYDLTGLKPGTEYAVWIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS17ERSYDLTGLKPGTEYKVAIHGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS18 ERSYDLTGLKPGTEYKVWIAGVKGGASSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS19ERSYDLTGLKPGTEYKVWIHGVKGGSSSPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS20 ERSYDLTGLKPGTEYKVWIHGVKGGAASPPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS21ERSYDLTGLKPGTEYKVWIHGVKGGASSAPLIARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS22 ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLAARFTT MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFNIAYWEPGIGGEAIWLRVPGS23ERSYDLTGLKPGTEYKVWIHGVKGGASSPPLIAAFTT

[0245] In some embodiments, the albumin binding domain polypeptide is isolated. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least, or is. 85%. 86%. 87%. 88%. 89%. 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%. 98%. or 99% identical to any of SEQ ID NO: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, the albumin binding domain comprises an amino acid sequence that is at least, or is, 85%, 86%, 87%, 88%, 89%, 90%, 901%, 92%, 93%, 94%, 95%. 96%. 97%. 98%. or 99% identical to any of SEQ ID NO: 5. 6, 7, 8, 9, 10, 11. 12. 13. 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, provided that the amino acid sequence has a substitution that corresponds to position 10 of any of SEQ ID NO: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, the substitution is A10V. In some embodiments, the substitution is A10G, A10L, A10I, A10T, or A10S. In some embodiments, the substitution at position 10 is any naturally occurring amino acid. In some embodiments, the isolated albumin binding domain comprises an amino acid sequence that has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 substitutions when compared to the amino acid sequence of SEQ ID NO: 5. 6, 7, 8, 9, 10, 11, 12. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. In some embodiments, the substitution is at a position that corresponds to position 10 of SEQ ID NO: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0246] In some embodiments, FN3 domains provided herein comprise a cysteine residue in at least one residue position corresponding to residue positions 6, 11, 22, 25. 26,- 88 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT52, 53, 61, 88 or positions 6, 8, 10, 11, 14, 15, 16, 20, 30, 34, 38, 40, 41, 45, 47, 48, 53, 54, 59, 60, 62, 64, 70, 88, 89, 90, 91, or 93 of SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, or at a C-terminus. Although the positions are listed in a series, each position can also be chosen individually. In some embodiments, the cysteine is at a position that corresponds to position 6, 53, or 88. In some embodiments, additional examples of albumin binding domains can be found in U. S. Patent No. 10,925,932, which is hereby incorporated by reference in its entirety.

[0247] In some embodiments, C can also be Endoporter, INF-7, TAT, polyarginine, polylysine, or an amphipathic peptide. These moieties can be used in place of or in addition to other half-life extending moieties provided for herein. In some embodiments, C can be a molecule that delivers the complex into the cell, the endosome, or the ER; said molecules are selected from those peptides listed in Table 2.Table 2: Transporter PeptidesSEQ ID NO: Name Amino Acid Sequence24 TAT RKKRRQRRR25 Penetratin RQ I K I WF QNRRMKWKK26 Transportan GWTLNSAGYLLGKINKALAALAKKIL27 MAP KLALKLALKALKAALKLA28 Pep-1 KETWWETWWTEWSQPKKKRKV29 KDEL KDEL30 GALA WEAALAEALAELAEHLAEALAEALEALAA31 HA2 GDIMGEWGNEIFGAIAGFLGC32 Aurine 1.2 GLFD I IKKIAESF33 MPG GALF LGWLGAAGS TMGAP KSKRKV34 TP-10 AGYLLGKINLKALAALAKKIL35 EB-1 LIRLWSHLIHIWFQNRRLKWKKK36 HA2-Penetratin GLFGAIAGF IENGWEGMIDGRQIKIWFQNRRMKWKK37 Endosomolytic FFKKLAHALHLLALLALHLAHALKKA38 Endosomolytic LFEAIEGFIENGWGMIDGWYG39 Endosomolytic LF E A I E GF I E NGWE GMI D GWYGRKKRRQRRR40 Endosomolytic IGAVLKVLTTGLPALISWIKRKRQQ41 ER Targeting MKLAVTLTLVTLALSSSSASA42 ER Targeting RLIEDICLPRWGCLWEDDKDEL43 ER Targeting MIRTLLLSTLVAGALSK44 ER Targeting ILSSLTVTQLLRRLHQWIK45 ER Targeting MIRTLLLSTLVAGALSKDEL

[0248] In some embodiments, Li is any linker that can be used to link the polymer C to the sense strand Xs or to link the polypeptide of Fi to the sense strand Xs. In some embodiments, Li has a formula of (Chemical formulas XA-L):- 89 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTVO. i,0. / XZX / OH Xs / XAs p Y Xs / XAsXs / XAs^0'pePtid^Y0HXS / XAS^0" Pz°'x / 1o / 'X°'' Peptid^y0HY O(Chemical formulas XA-L)wherein Xs, XAS, and Fi are as defined above.

[0249] In some embodiments, n = 0-20. In some embodiments, R and R1 are independently methyl. In some embodiments, R and R1 are independently present or both are absent. In some embodiments, X and Y are independently S. In some embodiments, X and Y are independently present or absent. In some embodiments, Peptide is an enzymatically cleavable peptide, such as, but not limited to, Val-Cit, Vai- Ala, etc.

[0250] In some embodiments, L2 is any linker that can be used to link the polypeptide of Fl to the antisense strand XAS or to link the polymer C to the antisense strand XAS.

[0251] In some embodiments, L2 has a formula of in the complex of (Chemical formulas XIA-F):- 90 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTxe 00 xArO'P'°'-aVPeptid^NJ^NJ Y Fic> 'yChemical formulas XIA-Fwherein XAS and Fi are as defined above.

[0252] In some embodiments, n = 0-20. In some embodiments, R and R1 are independently methyl. In some embodiments, R and R1 are independently present or both are absent. In some embodiments, X and Y are independently S. In some embodiments, X and Y are independently present or absent. In some embodiments, Peptide is an enzymatically cleavable peptide, such as, but not limited to, Val-Cit, Vai- Ala, and the like.

[0253] In some embodiments, the linker is covalently attached to Fl through a cysteine residue present on Fl, which can be illustrated as follows (chemical formulas XII A-F):Chemical formulas XIIA-Fwherein Xs is a 5’ to 3’ oligonucleotide sense strand of a double stranded siRNA molecule; XAS is a 3’ to 5’ oligonucleotide antisense strand of a double stranded- 91 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsiRNA molecule; and Fi is a polypeptide comprising at least one FN3 domain, wherein Xs and XAS form a double stranded siRNA molecule.

[0254] In some embodiments, A1-B1 has a formula of Formula XIIIA (top) or Formula XIIIB (bottom):° (XIIIA) O o G(XIIIB) wherein C is the polymer, such as PEG, Endoporter, INF-7, TAT, polyarginine, polylysine, an amphipathic peptide, or as provided for herein; and Fi is a polypeptide comprising at least one FN3 domain. The sense and antisense strands are represented by the “N” notations, wherein each nucleotide represented by N, is independently, A, U, C, or G or a modified nucleobase, such as those provided for herein. The Ni nucleotides of the sense strand and the antisense strand represent the 5’ end of the respective strands. For clarity, although Formulas XIIIA and XIIIB utilize Ni, N2, N3, etc., in both the sense and the antisense strand, the nucleotide bases do not need to be the same and are not intended to be the same. The siRNA molecule that is illustrated in Formulas XIIIA and XIIIB would be complementary to a target sequence. For example, in some embodiments, the sense strand comprises a 2’ -O-methyl modified nucleotide with a phosphorothioate (PS) modified backbone at Ni and N2, a 2’- fluoro modified nucleotide at N, N7, Ns, N$>, N12, and N17, and a 2’-O-methyl modified nucleotide at N4, Ns, Ne, N10, N11, N13, N14, Nis, Ni6, Nis, and N19.

[0255] In some embodiments, the antisense strand comprises a vinyl phosphonate moiety attached to Ni, a 2’ -fluoro modified nucleotide with a phosphorothioate (PS) modified backbone at N2, a 2’-O-methyl modified nucleotide at N3, N4, Ns, Ne, N7, Ns, N9, N10, N11, N12, N13, NIS, Nie, N17, NIS, and N19, a 2’-fluoro modified nucleotide at N14, and a 2’-O- methyl modified nucleotide with a phosphorothioate (PS) modified backbone at N20 and N21.

[0256] In some embodiments, a compound having a formula of Formula XIVAo pO' (XIVA) or- 92 - TPTS / 200322635 1Attorney Docket No. ROO-037WO PATENT- -|T '-A xr X N2‘N2Cht1gN18N17N^M1sNuMl3htl2N11NwN9H^7NsNsN4N3N2N1(XIVB)is provided. In some embodiments, the siRNA molecule is conjugated to the linker as set forth in formulas XIVA and / or XIVB, wherein n=l. In some embodiments, the siRNA molecule is conjugated to the linker as set forth in formulas XIVA and / or XIVB, wherein n=2. In some embodiments, the siRNA molecule is conjugated to the linker as set forth in formulas XIVA and / or XIVB, wherein n=3. In some embodiments, the siRNA molecule is conjugated to the linker as set forth in formulas XIVA and / or XIVB, wherein n=4. In some embodiments, the siRNA molecule is conjugated to the linker as set forth in formulas XIVA and / or XIVB, wherein n=5.

[0257] In some embodiments, a compound having a formula of Formula XVA (top) or Formula XVB (bottom):N-i^^NjNjNgNyNgNgN-^N^ ^i^oNigN-igNiyNigNisN^N-^N^N-iiN-ioNgNgNyNgNs^^^N-i HO(XVA)N1N2N3N4N5N6N7N8N9N1oN11N12N13N14N15N16N17N18N19-0>; X^Hr'N N21N2ON19N18N17N16N15N14N13N12N11N1ON9N8N7N6N5N4N3N2N1Y X H1 (XVB) is provided, wherein Fi is a polypeptide comprising at least one FN3 domain and is conjugated to a linker. The linker illustrated above, is a non-limiting example, and other types of linkers can be used.

[0258] In some embodiments, Fi comprises polypeptide having a formula of (Xi)n- (X2)q-(X3)y, wherein Xi is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; wherein n, q, and y are each independently 0 or 1, provided that at least one of n, q, and y is 1. In some embodiments, n, q, and y are each 1. In some embodiments, n and q are 1 and y is 0. In some embodiments n and y are 1 and q is 0.

[0259] In some embodiments, Xi is a CD71 binding FN3 domain, such as one provided herein. In some embodiments, X2 is a CD71 binding FN3 domain. In some embodiments, Xi and X2 are the same CD71 binding FN3 domains. In some embodiments, Xi and X2 are different CD71 binding FN3 domains. In some embodiments, X3 is a FN3 domain that binds to human serum albumin. In some embodiments, X3 is an Fc domain - 93 - TPTS / 200322635 1Attorney Docket No. ROO-037WO PATENTwithout effector function that extends the half-life of a protein. In some embodiments, Xi is a first CD71 binding FN3 domain, X2 is a second CD71 binding FN3 domain, and X3 is an albumin binding FN3 domain. Examples of such polypeptides are provided herein and below. In some embodiments, compositions are provided herein having a formula of C-(Xi)n-(X2)q-(Xs)y-L-X4, wherein C is a polymer, such as PEG, Endoporter, INF-7, TAT, polyarginine, polylysine, an amphipathic peptide, or peptides provided in Table 2; Xi is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; and X4 is a nucleic acid molecule, wherein n, q, and y are each independently 0 or 1.

[0260] In some embodiments, compositions are provided herein having a formula of (Xl)n-(X2)q-(X3)y-L-X4-C, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; X4 is a nucleic acid molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1.

[0261] In some embodiments, compositions are provided herein having a formula of X4-L-(Xl)n-(X2)q-(X3)y, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; and X4 is a nucleic acid molecule, wherein n, q, and y are each independently 0 or 1.

[0262] In some embodiments, compositions are provided herein having a formula of C-X4-L-(Xl)n-(X2)q-(X3)y, wherein C is a polymer; XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; and X4 is a nucleic acid molecule, wherein n, q, and y are each independently 0 or 1.

[0263] In some embodiments, compositions are provided herein having a formula of X4-L-(Xl)n-(X2)q-(X3)y-C, wherein XI is a first FN3 domain; X2 is a second FN3 domain; X3 is a third FN3 domain or half-life extender molecule; L is a linker; X4 is a nucleic acid molecule; and C is a polymer, wherein n, q, and y are each independently 0 or 1.

[0264] In some embodiments, the nucleic acid molecule is an siRNA pair. In some embodiments, the siRNA pair may follow the sequence: sense strand (5’-3’) nsnsnnnnNfNfNfnnnnnnnnsnsa or (5’-3’) nsnsnnnnNfNfNfnnnnnnnnna; and antisense strand (5’-3’) UfsNfsnnnNfnnnnnnnNfnNfnnnsusu, wherein (n) is 2’-O-Me (methyl), (Nf) is 2’-F (fluoro), (s) is phosphorothioate backbone modification. Each nucleotide in both the sense and antisense strands may be modified independently or in combination at ribosugar and nucleobase positions.

[0265] In some embodiments, compositions are provided herein comprising one or more FN3 domains conjugated to an siRNA molecule comprising a sense strand and an - 94 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTantisense strand that targets IFIH1, such as those provided for herein. In some embodiments, the composition comprises an siRNA molecule that does not contain any modified nucleobases. In some embodiments, the siRNA molecule further comprises a linker. In some embodiments, the linker is covalently attached to the sense strand or the antisense strand. In some embodiments, the linker is covalently attached to the sense strand. In some embodiments, the linker is covalently attached to the antisense strand. In some embodiments, the linker is covalently attached to the 5’ end of the sense strand or the antisense strand. In some embodiments, the linker is covalently attached to the 5’ end of the sense strand. In some embodiments, the linker is covalently attached to the 5’ end of the antisense strand. In some embodiments, the linker is covalently attached to the 3’ end of the sense strand or the antisense strand. In some embodiments, the linker is covalently attached to the 3’ end of the sense strand. In some embodiments, the linker is covalently attached to the 3’ end of the antisense strand.

[0266] In some embodiments, the siRNA molecule further comprises a vinyl phosphonate modification that is attached to the 5’ or the 3’ end of the sense strand or the antisense strand.

[0267] In some embodiments, the siRNA molecule comprises a sequence pair as set forth in Table 3 a or Table 3b, below. In some embodiments, the siRNA molecules does not include a 2’-0 methyl vinyl phosphonate uridine as the 5’ nucleotide on the antisense strand of the siRNA molecule.

[0268] In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleobase sequence selected from SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 158, SEQ ID NO: 159, SEQ ID NO: 160, SEQ ID NO: 161,- 95 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTSEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 188, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 224, SEQ ID NO: 225, SEQ ID NO: 1917 and SEQ ID NO: 1918.

[0269] In some embodiments, the sense strand comprises a sequence that is at least 90% identical to a nucleic acid sequence selected from SEQ ID NO: 250, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO 253, SEQ ID NO: 254, SEQ ID NO: 255, SEQ ID NO: 256, SEQ ID NO: 257, SEQ ID NO 258, SEQ ID NO: 259, SEQ ID NO: 260, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO 263, SEQ ID NO: 264, SEQ ID NO: 265, SEQ ID NO: 266, SEQ ID NO: 267, SEQ ID NO 268, SEQ ID NO: 269, SEQ ID NO: 270, SEQ ID NO: 271, SEQ ID NO: 272, SEQ ID NO 273, SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 277, SEQ ID NO 278, SEQ ID NO: 279, SEQ ID NO: 280, SEQ ID NO: 281, SEQ ID NO: 282, SEQ ID NO 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO 298, SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO 308. SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO 313. SEQ ID NO: 314, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO 318, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, SEQ ID NO: 322, SEQ ID NO 323, SEQ ID NO: 324, SEQ ID NO: 325, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO 328, SEQ ID NO: 329, SEQ ID NO: 330, SEQ ID NO: 331, SEQ ID NO: 332, SEQ ID NO 333, SEQ ID NO: 334, SEQ ID NO: 335, SEQ ID NO: 336, SEQ ID NO: 337, SEQ ID NO 338, SEQ ID NO: 339, SEQ ID NO: 340, SEQ ID NO: 341,- 96 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTSEQ ID NO: 342, SEQ ID NO: 343, SEQ ID NO: 344, SEQ ID NO: 345, SEQ ID NO: 346, SEQ ID NO: 347, SEQ ID NO: 348, SEQ ID NO: 349, SEQ ID NO: 350, SEQ ID NO: 351, SEQ ID NO: 352, SEQ ID NO: 353, SEQ ID NO: 354, SEQ ID NO: 355, SEQ ID NO: 356, SEQ ID NO: 357, SEQ ID NO: 358, SEQ ID NO: 359, SEQ ID NO: 360, SEQ ID NO: 361, SEQ ID NO: 362, SEQ ID NO: 363, SEQ ID NO: 364, SEQ ID NO: 365, SEQ ID NO: 366, SEQ ID NO: 367, SEQ ID NO: 368. SEQ ID NO: 369, SEQ ID NO: 370, SEQ ID NO: 371, SEQ ID NO: 372, SEQ ID NO: 373, SEQ ID NO: 374, and SEQ ID NO: 375.

[0270] In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 100. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 101. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 102. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 103. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 104. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 105. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 106. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 107. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 108. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 109. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 110. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 111. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 112. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 113. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 114. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 115. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 116. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 117. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 118. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 119. In - 97 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsome embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 120. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 121. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 122. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 123. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 124. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 125. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 126. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 127. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 128. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 129. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 130. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 131. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 132. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 133. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 134. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 135. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 136. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 137. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 138. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 139. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 140. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 141. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 142. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 143. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 144. In some embodiments, the sense strand comprises a nucleobase - 98 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsequence that is at least 90% identical to SEQ ID NO: 145. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 146. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 147. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 148. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 149. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 150. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 151. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 152. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 153. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 154. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 155. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 156. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 157. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 158. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 159. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 160. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 161. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 162. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 163. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 164. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 165. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 166. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 167. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 168. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 169. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 170. In - 99 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsome embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 171. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 172. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 173. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 174. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 175. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 176. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 177. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 178. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 179. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 180. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 181. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 182. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 183. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 184. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 185. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 186. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 187. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 188. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 189. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 190. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 191. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 192. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 193. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 194. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 195. In some embodiments, the sense strand comprises a nucleobase - 100 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsequence that is at least 90% identical to SEQ ID NO: 196. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 197. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 198. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 199. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 200. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 201. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 202. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 203. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 204. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 205. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 206. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 207. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 208. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 209. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 210. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 211. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 212. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 213. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 214. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 215. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 216. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 217. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 218. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 219. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 220. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 221. In - 101 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTsome embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 222. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 223. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 224. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 225. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 1917. In some embodiments, the sense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 1918.

[0271] In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 250. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 251. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 252. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 253. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 254. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 255. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 256. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 257. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 258. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 259. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 260. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 261. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 262. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 263. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 264. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 265. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 266. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 267. In some embodiments, the sense strand comprises a nucleic - 102 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTacid sequence that is at least 90% identical to SEQ ID NO: 268. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 569. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 270. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 271. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 272. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 273. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 274. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 275. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 276. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 277. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 278. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 279. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 280. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 281. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 282. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 283. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 284. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 285. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 286. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 287. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 288. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 289. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 290. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 291. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90%- 103 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTidentical to SEQ ID NO: 292. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 293. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 294. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 295. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 296. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 297. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 298. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 299. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 300. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 301. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 302. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 303. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 304. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 305. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 306. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 307. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 308. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 309. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 310. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 311. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 312. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 313. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 314. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 315. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 316. In some- 104 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTembodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 317. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 318. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 319. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 320. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 321. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 322. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 323. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 324. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 325. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 326. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 327. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 328. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 329. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 330. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 331. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 332. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 333. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 334. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 335. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 336. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 337. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 338. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 339. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 340. In some embodiments, the sense strand comprises a - 105 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTnucleic acid sequence that is at least 90% identical to SEQ ID NO: 341. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 342. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 343. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 344. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 345. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 346. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 347. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 348. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 349. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 350. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 351. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 352. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 353. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 354. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 355. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 356. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 357. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 358. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 359. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 360. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 361. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 362. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 363. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 364. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least - 106 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT90% identical to SEQ ID NO: 365. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 366. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 367. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 368. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 369. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 370. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 371. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 372. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 373. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 374. In some embodiments, the sense strand comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 375.

[0272] In some embodiments, the antisense strand is at least 90% identical to a nucleobase sequence selected from SEQ ID NO: 400, SEQ ID NO: 401, SEQ ID NO: 402, SEQ ID NO: 403, SEQ ID NO: 404, SEQ ID NO: 405, SEQ ID NO 406, SEQ ID NO: 407, SEQ ID NO: 408, SEQ ID NO: 409, SEQ ID NO: 410, SEQ ID NO 411, SEQ ID NO: 412, SEQ ID NO: 413, SEQ ID NO: 414, SEQ ID NO: 415, SEQ ID NO 416, SEQ ID NO: 417, SEQ ID NO: 418, SEQ ID NO: 419, SEQ ID NO: 420, SEQ ID NO 421, SEQ ID NO: 422, SEQ ID NO: 423, SEQ ID NO: 424, SEQ ID NO: 425, SEQ ID NO 426, SEQ ID NO: 427, SEQ ID NO: 428, SEQ ID NO: 429, SEQ ID NO: 430, SEQ ID NO 431, SEQ ID NO: 432, SEQ ID NO: 433, SEQ ID NO: 434, SEQ ID NO: 435, SEQ ID NO 436, SEQ ID NO: 437, SEQ ID NO: 438, SEQ ID NO: 439, SEQ ID NO: 440, SEQ ID NO 441, SEQ ID NO: 442, SEQ ID NO: 443, SEQ ID NO: 444, SEQ ID NO: 445, SEQ ID NO 446, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID NO: 449, SEQ ID NO: 450, SEQ ID NO 451, SEQ ID NO: 452, SEQ ID NO: 453, SEQ ID NO: 454, SEQ ID NO: 455, SEQ ID NO 456, SEQ ID NO: 457, SEQ ID NO: 458, SEQ ID NO: 459, SEQ ID NO: 460, SEQ ID NO 461, SEQ ID NO: 462, SEQ ID NO: 463, SEQ ID NO: 464, SEQ ID NO: 465, SEQ ID NO 466, SEQ ID NO: 467, SEQ ID NO: 468, SEQ ID NO: 469, SEQ ID NO: 470, SEQ ID NO 471, SEQ ID NO: 472, SEQ ID NO: 473, SEQ ID NO: 474, SEQ ID NO: 475, SEQ ID NO 476, SEQ ID NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID NO: 480, SEQ ID NO 481, SEQ ID NO: 482, SEQ ID NO: 483, SEQ ID NO: 484, SEQ ID NO: 485, SEQ ID NO 486, SEQ ID NO: 487,- 107 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTSEQ ID NO: 488, SEQ ID NO: 489, SEQ ID NO: 490, SEQ ID NO: 491, SEQ ID NO: 492 SEQ ID NO: 493, SEQ ID NO: 494, SEQ ID NO: 495, SEQ ID NO: 496, SEQ ID NO: 497 SEQ ID NO: 498, SEQ ID NO: 499, SEQ ID NO: 500, SEQ ID NO: 501, SEQ ID NO: 502 SEQ ID NO: 503, SEQ ID NO: 504, SEQ ID NO: 505, SEQ ID NO: 506, SEQ ID NO: 507 SEQ ID NO: 508, SEQ ID NO: 509, SEQ ID NO: 510, SEQ ID NO: 511, SEQ ID NO: 512 SEQ ID NO: 513, SEQ ID NO: 514, SEQ ID NO: 515, SEQ ID NO: 516, SEQ ID NO: 517 SEQ ID NO: 518, SEQ ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522 SEQ ID NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 1919, and SEQ ID NO: 1920.

[0273] In some embodiments, the antisense strand is at least 90% identical to a nucleic acid sequence selected from SEQ ID NO: 550, SEQ ID NO: 551. SEQ ID NO: 552, SEQ ID NO: 553, SEQ ID NO: 554, SEQ ID NO: 555, SEQ ID NO 556, SEQ ID NO: 557, SEQ ID NO: 558, SEQ ID NO: 559, SEQ ID NO: 560, SEQ ID NO 561, SEQ ID NO: 562, SEQ ID NO: 563, SEQ ID NO: 564, SEQ ID NO: 565, SEQ ID NO 566, SEQ ID NO: 567, SEQ ID NO: 568, SEQ ID NO: 569, SEQ ID NO: 570, SEQ ID NO 571, SEQ ID NO: 572, SEQ ID NO: 573, SEQ ID NO: 574, SEQ ID NO: 575, SEQ ID NO 576, SEQ ID NO: 577. SEQ ID NO: 578, SEQ ID NO: 579, SEQ ID NO: 580, SEQ ID NO 581, SEQ ID NO: 582, SEQ ID NO: 583, SEQ ID NO: 584, SEQ ID NO: 585, SEQ ID NO 586, SEQ ID NO: 587, SEQ ID NO: 588, SEQ ID NO: 589, SEQ ID NO: 590, SEQ ID NO 591, SEQ ID NO: 592, SEQ ID NO: 593, SEQ ID NO: 594, SEQ ID NO: 595, SEQ ID NO 596, SEQ ID NO: 597, SEQ ID NO: 598, SEQ ID NO: 599, SEQ ID NO: 600, SEQ ID NO 601, SEQ ID NO: 602, SEQ ID NO: 603, SEQ ID NO: 604, SEQ ID NO: 605, SEQ ID NO 606, SEQ ID NO: 607, SEQ ID NO: 608, SEQ ID NO: 609, SEQ ID NO: 610, SEQ ID NO 611, SEQ ID NO: 612, SEQ ID NO: 613, SEQ ID NO: 614, SEQ ID NO: 615, SEQ ID NO 616, SEQ ID NO: 617, SEQ ID NO: 618, SEQ ID NO: 619, SEQ ID NO: 620, SEQ ID NO 621, SEQ ID NO: 622, SEQ ID NO: 623, SEQ ID NO: 624, SEQ ID NO: 625, SEQ ID NO 626, SEQ ID NO: 627, SEQ ID NO: 628, SEQ ID NO: 629, SEQ ID NO: 630, SEQ ID NO 631, SEQ ID NO: 632, SEQ ID NO: 633, SEQ ID NO: 634, SEQ ID NO: 635, SEQ ID NO 636, SEQ ID NO: 637, SEQ ID NO: 638, SEQ ID NO: 639, SEQ ID NO: 640, SEQ ID NO 641, SEQ ID NO: 642, SEQ ID NO: 643, SEQ ID NO: 644, SEQ ID NO: 645, SEQ ID NO 646, SEQ ID NO: 647, SEQ ID NO: 648, SEQ ID NO: 649, SEQ ID NO: 650, SEQ ID NO 651, SEQ ID NO: 652, SEQ ID NO: 653, SEQ ID NO: 654, SEQ ID NO: 655, SEQ ID NO 656, SEQ ID NO: 657, SEQ ID NO: 658, SEQ ID NO: 659, SEQ ID NO: 660, SEQ ID NO 661, SEQ ID NO: 662, SEQ ID NO: 663, SEQ ID NO: 664, SEQ ID NO: 665, SEQ ID NO 666, SEQ ID NO: 667,- 108 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTSEQ ID NO: 668, SEQ ID NO: 669, SEQ ID NO: 670, SEQ ID NO: 671, SEQ ID NO: 672, SEQ ID NO: 673, SEQ ID NO: 674, and SEQ ID NO: 675.

[0274] In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 400. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 401. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 402. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 403. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 404. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 405. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 406. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 407. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 408. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 409. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 410. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 411. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 412. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 413. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 414. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 415. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 416. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 417. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 418. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 419. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 420. In some embodiments, the antisense strand comprises a- 109 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTnucleobase sequence that is at least 90% identical to SEQ ID NO: 421. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 422. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 423. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 424. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 425. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 426. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 427. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 428. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 429. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 430. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 431. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 432. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 433. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 434. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 435. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 436. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 437. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 438. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 439. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 440. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 441. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 442. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 443. In some- 110 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTembodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 444. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 445. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 446. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 447. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 448. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 449. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 450. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 451. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 452. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 453. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 454. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 455. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 456. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 457. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 458. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 459. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 460. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 461. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 462. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 463. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 464. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 465. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% - 111 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTidentical to SEQ ID NO: 466. In some embodiments, the antisense strand comprises a nucleobase sequence that is at least 90% identical to SEQ ID NO: 467. In some...

Claims

Attorney Docket No. ROO-037WO PATENTWHAT IS CLAIMED IS:

1. A composition comprising an siRNA molecule comprising a sense strand and an antisense strand that targets IFIH1 gene, wherein:the sense strand comprises a nucleobase sequence of SEQ ID NO: 116, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 416;the sense strand comprises a nucleobase sequence of SEQ ID NO: 100, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 400;the sense strand comprises a nucleobase sequence of SEQ ID NO: 101, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 401;the sense strand comprises a nucleobase sequence of SEQ ID NO: 102, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 402;the sense strand comprises a nucleobase sequence of SEQ ID NO: 103, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 403;the sense strand comprises a nucleobase sequence of SEQ ID NO: 104, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 404;the sense strand comprises a nucleobase sequence of SEQ ID NO: 105, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 405;the sense strand comprises a nucleobase sequence of SEQ ID NO: 106, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 406;the sense strand comprises a nucleobase sequence of SEQ ID NO: 107, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 407;the sense strand comprises a nucleobase sequence of SEQ ID NO: 108, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 408;the sense strand comprises a nucleobase sequence of SEQ ID NO: 109, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 409;the sense strand comprises a nucleobase sequence of SEQ ID NO: 110, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 410;the sense strand comprises a nucleobase sequence of SEQ ID NO: 111, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 411;- 361 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 112, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 412;the sense strand comprises a nucleobase sequence of SEQ ID NO: 113, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 413;the sense strand comprises a nucleobase sequence of SEQ ID NO: 114, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 414;the sense strand comprises a nucleobase sequence of SEQ ID NO: 115, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 415;the sense strand comprises a nucleobase sequence of SEQ ID NO: 117, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 417;the sense strand comprises a nucleobase sequence of SEQ ID NO: 118, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 418;the sense strand comprises a nucleobase sequence of SEQ ID NO: 119, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 419;the sense strand comprises a nucleobase sequence of SEQ ID NO: 120, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 420;the sense strand comprises a nucleobase sequence of SEQ ID NO: 121, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 421;the sense strand comprises a nucleobase sequence of SEQ ID NO: 122, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 422;the sense strand comprises a nucleobase sequence of SEQ ID NO: 123, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 423;the sense strand comprises a nucleobase sequence of SEQ ID NO: 124, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 424;the sense strand comprises a nucleobase sequence of SEQ ID NO: 125, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 425;the sense strand comprises a nucleobase sequence of SEQ ID NO: 126, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 426;- 362 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 127, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 427;the sense strand comprises a nucleobase sequence of SEQ ID NO: 128, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 428;the sense strand comprises a nucleobase sequence of SEQ ID NO: 129, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 429;the sense strand comprises a nucleobase sequence of SEQ ID NO: 130, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 430;the sense strand comprises a nucleobase sequence of SEQ ID NO: 131, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 431;the sense strand comprises a nucleobase sequence of SEQ ID NO: 132, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 432;the sense strand comprises a nucleobase sequence of SEQ ID NO: 133, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 433;the sense strand comprises a nucleobase sequence of SEQ ID NO: 134, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 434;the sense strand comprises a nucleobase sequence of SEQ ID NO: 135, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 435;the sense strand comprises a nucleobase sequence of SEQ ID NO: 136, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 436;the sense strand comprises a nucleobase sequence of SEQ ID NO: 137, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 437;the sense strand comprises a nucleobase sequence of SEQ ID NO: 138, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 438;the sense strand comprises a nucleobase sequence of SEQ ID NO: 139, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 439;the sense strand comprises a nucleobase sequence of SEQ ID NO: 140, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 440;- 363 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 141, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 441;the sense strand comprises a nucleobase sequence of SEQ ID NO: 142, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 442;the sense strand comprises a nucleobase sequence of SEQ ID NO: 143, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 443;the sense strand comprises a nucleobase sequence of SEQ ID NO: 144, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 444;the sense strand comprises a nucleobase sequence of SEQ ID NO: 145, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 445;the sense strand comprises a nucleobase sequence of SEQ ID NO: 146, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 446;the sense strand comprises a nucleobase sequence of SEQ ID NO: 147, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 447;the sense strand comprises a nucleobase sequence of SEQ ID NO: 148, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 448;the sense strand comprises a nucleobase sequence of SEQ ID NO: 149, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449;the sense strand comprises a nucleobase sequence of SEQ ID NO: 150, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450;the sense strand comprises a nucleobase sequence of SEQ ID NO: 151, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 451;the sense strand comprises a nucleobase sequence of SEQ ID NO: 152, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 452;the sense strand comprises a nucleobase sequence of SEQ ID NO: 153, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 453;the sense strand comprises a nucleobase sequence of SEQ ID NO: 154, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 454;- 364 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 155, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 455;the sense strand comprises a nucleobase sequence of SEQ ID NO: 156, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 456;the sense strand comprises a nucleobase sequence of SEQ ID NO: 157, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457;the sense strand comprises a nucleobase sequence of SEQ ID NO: 158, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 458;the sense strand comprises a nucleobase sequence of SEQ ID NO: 159, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 459;the sense strand comprises a nucleobase sequence of SEQ ID NO: 160, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 460;the sense strand comprises a nucleobase sequence of SEQ ID NO: 161, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 461;the sense strand comprises a nucleobase sequence of SEQ ID NO: 162, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 462;the sense strand comprises a nucleobase sequence of SEQ ID NO: 163, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 463;the sense strand comprises a nucleobase sequence of SEQ ID NO: 164, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 464;the sense strand comprises a nucleobase sequence of SEQ ID NO: 165, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 465;the sense strand comprises a nucleobase sequence of SEQ ID NO: 166, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 466;the sense strand comprises a nucleobase sequence of SEQ ID NO: 167, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 467;the sense strand comprises a nucleobase sequence of SEQ ID NO: 168, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 468;- 365 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 169, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 469;the sense strand comprises a nucleobase sequence of SEQ ID NO: 170, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 470;the sense strand comprises a nucleobase sequence of SEQ ID NO: 171, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 471;the sense strand comprises a nucleobase sequence of SEQ ID NO: 172, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 472;the sense strand comprises a nucleobase sequence of SEQ ID NO: 173, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 473;the sense strand comprises a nucleobase sequence of SEQ ID NO: 174, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 474;the sense strand comprises a nucleobase sequence of SEQ ID NO: 175, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 475;the sense strand comprises a nucleobase sequence of SEQ ID NO: 176, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 476;the sense strand comprises a nucleobase sequence of SEQ ID NO: 177, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 477;the sense strand comprises a nucleobase sequence of SEQ ID NO: 178, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 478;the sense strand comprises a nucleobase sequence of SEQ ID NO: 179, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 479;the sense strand comprises a nucleobase sequence of SEQ ID NO: 180, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 480;the sense strand comprises a nucleobase sequence of SEQ ID NO: 181, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 481;the sense strand comprises a nucleobase sequence of SEQ ID NO: 182, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 482;- 366 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 183, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 483;the sense strand comprises a nucleobase sequence of SEQ ID NO: 184, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 484;the sense strand comprises a nucleobase sequence of SEQ ID NO: 185, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 485;the sense strand comprises a nucleobase sequence of SEQ ID NO: 186, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 486;the sense strand comprises a nucleobase sequence of SEQ ID NO: 187, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 487;the sense strand comprises a nucleobase sequence of SEQ ID NO: 188, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 488;the sense strand comprises a nucleobase sequence of SEQ ID NO: 189, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 489;the sense strand comprises a nucleobase sequence of SEQ ID NO: 190, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 490;the sense strand comprises a nucleobase sequence of SEQ ID NO: 191, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 491;the sense strand comprises a nucleobase sequence of SEQ ID NO: 192, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 492;the sense strand comprises a nucleobase sequence of SEQ ID NO: 193, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 493;the sense strand comprises a nucleobase sequence of SEQ ID NO: 194, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 494;the sense strand comprises a nucleobase sequence of SEQ ID NO: 195, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 495;the sense strand comprises a nucleobase sequence of SEQ ID NO: 196, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 496;- 367 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 197, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 497;the sense strand comprises a nucleobase sequence of SEQ ID NO: 198, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 498;the sense strand comprises a nucleobase sequence of SEQ ID NO: 199, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 499;the sense strand comprises a nucleobase sequence of SEQ ID NO: 200, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 500;the sense strand comprises a nucleobase sequence of SEQ ID NO: 201, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 501;the sense strand comprises a nucleobase sequence of SEQ ID NO: 202, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 502;the sense strand comprises a nucleobase sequence of SEQ ID NO: 203, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 503;the sense strand comprises a nucleobase sequence of SEQ ID NO: 204, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 504;the sense strand comprises a nucleobase sequence of SEQ ID NO: 205, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 505;the sense strand comprises a nucleobase sequence of SEQ ID NO: 206, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 506;the sense strand comprises a nucleobase sequence of SEQ ID NO: 207, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 507;the sense strand comprises a nucleobase sequence of SEQ ID NO: 208, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 508;the sense strand comprises a nucleobase sequence of SEQ ID NO: 209, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 509;the sense strand comprises a nucleobase sequence of SEQ ID NO: 210, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 510;- 368 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 211, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 511;the sense strand comprises a nucleobase sequence of SEQ ID NO: 212, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 512;the sense strand comprises a nucleobase sequence of SEQ ID NO: 213, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 513;the sense strand comprises a nucleobase sequence of SEQ ID NO: 214, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 514;the sense strand comprises a nucleobase sequence of SEQ ID NO: 215, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 515;the sense strand comprises a nucleobase sequence of SEQ ID NO: 216, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 516;the sense strand comprises a nucleobase sequence of SEQ ID NO: 217, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 517;the sense strand comprises a nucleobase sequence of SEQ ID NO: 218, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 518;the sense strand comprises a nucleobase sequence of SEQ ID NO: 219, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 519;the sense strand comprises a nucleobase sequence of SEQ ID NO: 220, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 520;the sense strand comprises a nucleobase sequence of SEQ ID NO: 221, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 521;the sense strand comprises a nucleobase sequence of SEQ ID NO: 222, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 522;the sense strand comprises a nucleobase sequence of SEQ ID NO: 223, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 523;the sense strand comprises a nucleobase sequence of SEQ ID NO: 224, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 524;- 369 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 225, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 525;the sense strand comprises a nucleobase sequence of SEQ ID NO: 1917, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1919; or the sense strand comprises a nucleobase sequence of SEQ ID NO: 1918, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1920.

2. The composition of claim 1, wherein the siRNA molecule comprises a linker covalently attached to the sense strand or the antisense strand.

3. The composition of claim 2, wherein the linker is TEG-Propyl-Mal, having the formula shown below:

4. The composition of claim 2, wherein the linker is Cg-NFE-Propyl Mai, having the formula shown below:

5. The composition of any one of claims 1-4, further comprising a vinyl phosphonate modification on one or both of the sense strand or the antisense strand.

6. The composition of claim 5, wherein the vinyl phosphonate modification is attached to a 5' end or a 3' end of the sense strand or the antisense strand.

7. The composition of any one of claims 1-6. wherein the siRNA molecule has a formula as shown in the following formula (Formula IX):N1N2N3N4N5N6N7N8N9N10N11N12N13N14N15N16N17N18N19 Sense strand (SS), 5'-3’N21N20N 19N18N 17N 16N15N 14N 13N 12N11N 10N9N8N7N6N5N4N3N2N 1 Antisense strand (AS) 3’-5\- 370 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTwherein each nucleotide, represented by N, is independently A, U, C, or G, or a modified nucleotide base, such as those provided for herein.

8. The composition of claim 7, wherein the sense strand comprises a 2’0-methyl modified nucleotide with a phosphorothioate (PS) modified backbone at Ni and N2, a 2’- fluoro modified nucleotide at N3, N7, Ns, Ns>, N12, and N17, and a 2’0-methyl modified nucleotide at N4, Ns, Ne, N10, N11, N13, N14, Nis. Ni6, Nis, and N19.

9. The composition of claim 7, wherein the antisense strand comprises a vinyl phosphonate moiety at Ni, a 2’-fluoro modified nucleotide with a phosphorothioate (PS) modified backbone at N2, a 2’0-methyl modified nucleotide at N3, N4, Ns, Ne, N7, Ns, N9, N10, N11, N12, N13, Nis, Nie, N17, NIS, and N19, a 2’-fluoro modified nucleotide at N14, and a 2’0-methyl modified nucleotide with a phosphorothioate (PS) modified backbone at N20 and N21.

10. The composition of claim 7, wherein a vinyl phosphonate moiety is attached to Ni of the antisense strand.

11. The composition of any one of claims 7-10, wherein the siRNA molecule is conjugated to a linker as shown in the following formula (Formula XIVA (top) Formula XI VB (bottom):G 00, or12. The composition of claim 11, wherein n = 3.

13. The composition of any one of claims 7-12, wherein the siRNA molecule has the formula as shown in the following formulas (Formula XVAtop; Formula XVB bottom)- 371 - TPTS / 200322635 1Attorney Docket No. ROO-037WO PATENTt> o;N » \ T. K / t 'X N'X1 VI hX1 Y ' ""H H / > O H0 V; OH y X"' ‘ " H.. L^y>"'S<f" ” h wherein Fi is a polypeptide comprising at least one FN3 domain.

14. The composition of any one of claims 1-13, wherein:the sense strand comprises a nucleic acid sequence of SEQ ID NO: 266, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 566;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 250, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 550;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 251, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 551;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 252, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 552;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 253, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 553;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 254, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 554;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 255, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 555;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 256, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 556;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 257, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 557;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 258, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 558;- 372 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 259, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 559;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 260, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 560;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 261, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 561;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 262, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 562;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 263, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 563;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 264, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 564;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 265, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 565;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 267, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 567;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 268, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 568;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 269, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 569;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 270, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 570;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 271, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 571;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 272, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 572;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 273, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 573;- 373 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 274, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 574;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 275, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 575;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 276, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 576;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 277, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 577;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 278, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 578;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 279, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 579;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 280, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 580;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 281, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 581;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 282, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 582;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 283, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 583;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 284, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 584;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 285, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 585;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 286, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 586;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 287, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 587;- 374 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 288, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 588;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 289, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 589;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 290, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 590;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 291, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 591;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 292, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 592;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 293, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 593;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 294, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 594;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 295, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 595;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 296, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 596;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 297, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 597;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 298, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 598,;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 299, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 599;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 300, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 600;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 301, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 601;- 375 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 302, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 602;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 303, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 603;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 304, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 604;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 305, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 605;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 306, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 606;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 307, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 607;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 308, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 608;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 309, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 609;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 310, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 610;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 311, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 611;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 312, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 612;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 313, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 613;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 314, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 614;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 315, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 615;- 376 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 316, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 616;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 317, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 617;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 318, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 618;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 319, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 619;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 320, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 620;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 321, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 621;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 322, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 622;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 323, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 623;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 324, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 624;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 325, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 625;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 326, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 626;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 327, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 627;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 328, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 628;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 329, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 629;- 377 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 330, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 630;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 331, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 631;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 332, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 632;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 333, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 633;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 334, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 634;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 335, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 635;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 336, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 636;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 337, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 637;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 338, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 638;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 339, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 639;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 340, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 640;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 341, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 641;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 342, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 642;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 343, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 643;- 378 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 344, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 644;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 345, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 645;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 346, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 646;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 347, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 647;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 348, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 648;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 349, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 649;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 350, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 650;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 351, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 651;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 352, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 652;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 353, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 653;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 354, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 654;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 355, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 655;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 356, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 656;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 357, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 657;- 379 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 358, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 658;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 359, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 659;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 660;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 661;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 662;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 363, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 663;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 364, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 664;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 365, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 665;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 366, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 666;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 367, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 667;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 368, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 668;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 369, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 669;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 370, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 670;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 371, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 671;- 380 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 372, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 672;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 673;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 374, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 674; or the sense strand comprises a nucleic acid sequence of SEQ ID NO: 375, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 675.

17. The composition of any one of claims 1-16, further comprising one or more FN3 domains conjugated to the siRNA molecule.

18. The composition of claim 17, wherein the FN3 domain is conjugated to the siRNA molecule through a cysteine in the FN3 domain.

19. The composition of claim 17 or 18, wherein the cysteine is located at a position that corresponds to residue 6, 8, 10, 11, 14, 15, 16. 20, 30, 34, 38, 40, 41, 45, 47, 48, 53, 54, 59, 60, 62, 64, 70, 88, 89, 90, 91, or 93 of the FN3 domain based on SEQ ID NO: 1 of U. S. Patent No. 10,196,446.

20. The composition of claim 19, wherein the cysteine is located at a position that corresponds to residue 6, 53, or 88 of the FN3 domain based on SEQ ID NO: 1 of U. S. Patent No. 10.196,446.

21. The composition of any one of claims 17-20, wherein the one or more FN3 domains comprises an FN3 domain that binds to CD71.

22. The composition of claim 21, wherein the FN3 domain comprises an amino acid sequence that is at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, or is identical to a sequence selected from SEQ ID NOs: 1205, 1000-1204, and 1206-1745.

23. The composition of claim 22, wherein the FN3 domain comprises an amino acid sequence selected from SEQ ID NOs: 1205, 1000-1204, and 1206-1745.

24. The composition of any one of claims 17-23, wherein the one or more FN3 domains comprises a first FN3 domain and a second FN3 domain linked by a peptide linker.- 381 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT25. The composition of claim 24, wherein the linker comprises an amino acid sequence selected from SEQ ID NOs: 1900-1916.

26. The composition of any one of claims 24 or 25, wherein:the first FN3 domain comprises an amino acid sequence that is at least 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to or is identical to a sequence selected from any of SEQ ID NOs: 1205, 1000-1204, and 1206-1745; andthe second FN3 domain comprises an amino acid sequence that is at least 87%. 88%. 89%. 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%. 98%. or 99% identical to or is identical to a sequence selected from SEQ ID NO: 1205, 1000-1204, and 1206-1745.

27. The composition of any one of claims 24-26, wherein the first FN3 domain and the second FN3 domain bind to different proteins.

28. The composition of any one of claims 24-26, wherein the first FN3 domain and the second FN3 domain bind to the same protein.

29. The composition of any one of claims 87-93, wherein the first FN3 domain binds to CD71.

30. The composition of claim 94, wherein the second FN3 domain binds to a different target that does not bind CD71 or wherein the second FN3 domain does not bind CD71.

31. The composition of claim 95, wherein the second FN3 domain binds to albumin and comprises an amino acid sequence selected from SEQ ID NOs: 5-23, or a binding fragment thereof.

32. The composition of any one of claims 17-31, further comprising a third FN3 domain.

33. The composition of claim 32, wherein the third FN3 domain binds to CD71 or albumin.

34. The composition of claim 33, wherein the third FN3 domain binds CD71 and comprises an amino acid sequence as provided for herein, including but not limited to SEQ ID NO: 1205, 1000-1204, and 1206-1745, or a binding fragment thereof.- 382 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT35. The composition of claim 33, wherein the third FN3 domain binds albumin and comprises an amino acid sequence as provided for herein, including but not limited to SEQ ID NOs: 5-23, or a binding fragment thereof.

36. The composition of any one of claims 32-35, wherein the third FN3 domain has a cysteine substitution as provided for herein.

37. A composition comprising a FN3 polypeptide domain linked to an siRNA molecule comprising a sense strand and an antisense strand that targets IFIH1 gene,wherein the FN3 polypeptide domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 1205, andwherein the siRNA molecule comprises:the sense strand comprises a nucleobase sequence of SEQ ID NO: 116, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 416;the sense strand comprises a nucleobase sequence of SEQ ID NO: 100, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 400;the sense strand comprises a nucleobase sequence of SEQ ID NO: 101, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 401;the sense strand comprises a nucleobase sequence of SEQ ID NO: 102, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 402;the sense strand comprises a nucleobase sequence of SEQ ID NO: 103, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 403;the sense strand comprises a nucleobase sequence of SEQ ID NO: 104, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 404;the sense strand comprises a nucleobase sequence of SEQ ID NO: 105, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 405;the sense strand comprises a nucleobase sequence of SEQ ID NO: 106, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 406;the sense strand comprises a nucleobase sequence of SEQ ID NO: 107, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 407;- 383 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 108, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 408;the sense strand comprises a nucleobase sequence of SEQ ID NO: 109, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 409;the sense strand comprises a nucleobase sequence of SEQ ID NO: 110, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 410;the sense strand comprises a nucleobase sequence of SEQ ID NO: 111, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 411;the sense strand comprises a nucleobase sequence of SEQ ID NO: 112, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 412;the sense strand comprises a nucleobase sequence of SEQ ID NO: 113, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 413;the sense strand comprises a nucleobase sequence of SEQ ID NO: 114, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 414;the sense strand comprises a nucleobase sequence of SEQ ID NO: 115, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 415;the sense strand comprises a nucleobase sequence of SEQ ID NO: 117, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 417;the sense strand comprises a nucleobase sequence of SEQ ID NO: 118, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 418;the sense strand comprises a nucleobase sequence of SEQ ID NO: 119, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 419;the sense strand comprises a nucleobase sequence of SEQ ID NO: 120, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 420;the sense strand comprises a nucleobase sequence of SEQ ID NO: 121, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 421;the sense strand comprises a nucleobase sequence of SEQ ID NO: 122, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 422;- 384 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 123, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 423;the sense strand comprises a nucleobase sequence of SEQ ID NO: 124, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 424;the sense strand comprises a nucleobase sequence of SEQ ID NO: 125, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 425;the sense strand comprises a nucleobase sequence of SEQ ID NO: 126, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 426;the sense strand comprises a nucleobase sequence of SEQ ID NO: 127, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 427;the sense strand comprises a nucleobase sequence of SEQ ID NO: 128, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 428;the sense strand comprises a nucleobase sequence of SEQ ID NO: 129, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 429;the sense strand comprises a nucleobase sequence of SEQ ID NO: 130, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 430;the sense strand comprises a nucleobase sequence of SEQ ID NO: 131, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 431;the sense strand comprises a nucleobase sequence of SEQ ID NO: 132, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 432;the sense strand comprises a nucleobase sequence of SEQ ID NO: 133, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 433;the sense strand comprises a nucleobase sequence of SEQ ID NO: 134, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 434;the sense strand comprises a nucleobase sequence of SEQ ID NO: 135, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 435;the sense strand comprises a nucleobase sequence of SEQ ID NO: 136, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 436;- 385 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 137, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 437;the sense strand comprises a nucleobase sequence of SEQ ID NO: 138, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 438;the sense strand comprises a nucleobase sequence of SEQ ID NO: 139, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 439;the sense strand comprises a nucleobase sequence of SEQ ID NO: 140, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 440;the sense strand comprises a nucleobase sequence of SEQ ID NO: 141, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 441;the sense strand comprises a nucleobase sequence of SEQ ID NO: 142, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 442;the sense strand comprises a nucleobase sequence of SEQ ID NO: 143, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 443;the sense strand comprises a nucleobase sequence of SEQ ID NO: 144, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 444;the sense strand comprises a nucleobase sequence of SEQ ID NO: 145, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 445;the sense strand comprises a nucleobase sequence of SEQ ID NO: 146, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 446;the sense strand comprises a nucleobase sequence of SEQ ID NO: 147, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 447;the sense strand comprises a nucleobase sequence of SEQ ID NO: 148, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 448;the sense strand comprises a nucleobase sequence of SEQ ID NO: 149, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 449;the sense strand comprises a nucleobase sequence of SEQ ID NO: 150, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 450;- 386 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 151, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 451;the sense strand comprises a nucleobase sequence of SEQ ID NO: 152, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 452;the sense strand comprises a nucleobase sequence of SEQ ID NO: 153, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 453;the sense strand comprises a nucleobase sequence of SEQ ID NO: 154, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 454;the sense strand comprises a nucleobase sequence of SEQ ID NO: 155, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 455;the sense strand comprises a nucleobase sequence of SEQ ID NO: 156, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 456;the sense strand comprises a nucleobase sequence of SEQ ID NO: 157, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 457;the sense strand comprises a nucleobase sequence of SEQ ID NO: 158, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 458;the sense strand comprises a nucleobase sequence of SEQ ID NO: 159, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 459;the sense strand comprises a nucleobase sequence of SEQ ID NO: 160, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 460;the sense strand comprises a nucleobase sequence of SEQ ID NO: 161, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 461;the sense strand comprises a nucleobase sequence of SEQ ID NO: 162, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 462;the sense strand comprises a nucleobase sequence of SEQ ID NO: 163, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 463;the sense strand comprises a nucleobase sequence of SEQ ID NO: 164, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 464;- 387 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 165, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 465;the sense strand comprises a nucleobase sequence of SEQ ID NO: 166, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 466;the sense strand comprises a nucleobase sequence of SEQ ID NO: 167, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 467;the sense strand comprises a nucleobase sequence of SEQ ID NO: 168, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 468;the sense strand comprises a nucleobase sequence of SEQ ID NO: 169, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 469;the sense strand comprises a nucleobase sequence of SEQ ID NO: 170, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 470;the sense strand comprises a nucleobase sequence of SEQ ID NO: 171, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 471;the sense strand comprises a nucleobase sequence of SEQ ID NO: 172, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 472;the sense strand comprises a nucleobase sequence of SEQ ID NO: 173, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 473;the sense strand comprises a nucleobase sequence of SEQ ID NO: 174, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 474;the sense strand comprises a nucleobase sequence of SEQ ID NO: 175, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 475;the sense strand comprises a nucleobase sequence of SEQ ID NO: 176, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 476;the sense strand comprises a nucleobase sequence of SEQ ID NO: 177, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 477;the sense strand comprises a nucleobase sequence of SEQ ID NO: 178, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 478;- 388 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 179, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 479;the sense strand comprises a nucleobase sequence of SEQ ID NO: 180, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 480;the sense strand comprises a nucleobase sequence of SEQ ID NO: 181, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 481;the sense strand comprises a nucleobase sequence of SEQ ID NO: 182, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 482;the sense strand comprises a nucleobase sequence of SEQ ID NO: 183, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 483;the sense strand comprises a nucleobase sequence of SEQ ID NO: 184, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 484;the sense strand comprises a nucleobase sequence of SEQ ID NO: 185, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 485;the sense strand comprises a nucleobase sequence of SEQ ID NO: 186, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 486;the sense strand comprises a nucleobase sequence of SEQ ID NO: 187, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 487;the sense strand comprises a nucleobase sequence of SEQ ID NO: 188, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 488;the sense strand comprises a nucleobase sequence of SEQ ID NO: 189, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 489;the sense strand comprises a nucleobase sequence of SEQ ID NO: 190, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 490;the sense strand comprises a nucleobase sequence of SEQ ID NO: 191, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 491;the sense strand comprises a nucleobase sequence of SEQ ID NO: 192, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 492;- 389 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 193, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 493;the sense strand comprises a nucleobase sequence of SEQ ID NO: 194, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 494;the sense strand comprises a nucleobase sequence of SEQ ID NO: 195, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 495;the sense strand comprises a nucleobase sequence of SEQ ID NO: 196, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 496;the sense strand comprises a nucleobase sequence of SEQ ID NO: 197, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 497;the sense strand comprises a nucleobase sequence of SEQ ID NO: 198, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 498;the sense strand comprises a nucleobase sequence of SEQ ID NO: 199, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 499;the sense strand comprises a nucleobase sequence of SEQ ID NO: 200, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 500;the sense strand comprises a nucleobase sequence of SEQ ID NO: 201, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 501;the sense strand comprises a nucleobase sequence of SEQ ID NO: 202, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 502;the sense strand comprises a nucleobase sequence of SEQ ID NO: 203, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 503;the sense strand comprises a nucleobase sequence of SEQ ID NO: 204, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 504;the sense strand comprises a nucleobase sequence of SEQ ID NO: 205, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 505;the sense strand comprises a nucleobase sequence of SEQ ID NO: 206, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 506;- 390 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 207, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 507;the sense strand comprises a nucleobase sequence of SEQ ID NO: 208, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 508;the sense strand comprises a nucleobase sequence of SEQ ID NO: 209, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 509;the sense strand comprises a nucleobase sequence of SEQ ID NO: 210, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 510;the sense strand comprises a nucleobase sequence of SEQ ID NO: 211, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 511;the sense strand comprises a nucleobase sequence of SEQ ID NO: 212, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 512;the sense strand comprises a nucleobase sequence of SEQ ID NO: 213, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 513;the sense strand comprises a nucleobase sequence of SEQ ID NO: 214, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 514;the sense strand comprises a nucleobase sequence of SEQ ID NO: 215, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 515;the sense strand comprises a nucleobase sequence of SEQ ID NO: 216, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 516;the sense strand comprises a nucleobase sequence of SEQ ID NO: 217, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 517;the sense strand comprises a nucleobase sequence of SEQ ID NO: 218, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 518;the sense strand comprises a nucleobase sequence of SEQ ID NO: 219, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 519;the sense strand comprises a nucleobase sequence of SEQ ID NO: 220, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 520;- 391 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleobase sequence of SEQ ID NO: 221, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 521;the sense strand comprises a nucleobase sequence of SEQ ID NO: 222, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 522;the sense strand comprises a nucleobase sequence of SEQ ID NO: 223, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 523;the sense strand comprises a nucleobase sequence of SEQ ID NO: 224, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 524;the sense strand comprises a nucleobase sequence of SEQ ID NO: 225, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 525;the sense strand comprises a nucleobase sequence of SEQ ID NO: 1917, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1919; or the sense strand comprises a nucleobase sequence of SEQ ID NO: 1918, and the antisense strand comprises a nucleobase sequence of SEQ ID NO: 1920, and wherein each nucleotide of the sense strand or the antisense strand is or is not a modified nucleotide.

38. The composition of claim 37, wherein a 5' end of the antisense strand further comprises a vinyl phosphonate modification and a 3' terminal nucleotide of the sense strand is attached to a linker.

39. The composition of claim 38, wherein:the sense strand comprises a nucleic acid sequence of SEQ ID NO: 266, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 566;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 250, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 550;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 251, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 551;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 252, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 552;- 392 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 253, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 553;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 254, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 554;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 255, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 555;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 256, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 556;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 257, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 557;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 258, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 558;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 259, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 559;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 260, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 560;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 261, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 561;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 262, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 562;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 263, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 563;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 264, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 564;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 265, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 565;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 267, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 567;- 393 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 268, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 568;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 269, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 569;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 270, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 570;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 271, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 571;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 272, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 572;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 273, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 573;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 274, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 574;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 275, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 575;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 276, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 576;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 277, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 577;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 278, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 578;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 279, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 579;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 280, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 580;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 281, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 581;- 394 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 282, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 582;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 283, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 583;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 284, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 584;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 285, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 585;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 286, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 586;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 287, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 587;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 288, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 588;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 289, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 589;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 290, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 590;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 291, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 591;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 292, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 592;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 293, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 593;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 294, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 594;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 295, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 595;- 395 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 296, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 596;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 297, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 597;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 298, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 598,;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 299, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 599;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 300, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 600;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 301, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 601;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 302, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 602;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 303, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 603;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 304, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 604;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 305, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 605;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 306, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 606;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 307, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 607;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 308, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 608;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 309, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 609;- 396 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 310, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 610;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 311, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 611;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 312, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 612;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 313, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 613;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 314, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 614;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 615;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 316, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 616;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 317, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 617;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 318, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 618;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 319, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 619;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 320, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 620;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 321, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 621;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 322, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 622;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 323, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 623;- 397 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 324, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 624;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 325, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 625;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 326, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 626;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 327, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 627;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 328, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 628;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 329, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 629;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 330, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 630;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 331, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 631;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 332, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 632;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 333, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 633;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 334, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 634;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 335, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 635;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 336, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 636;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 337, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 637;- 398 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 338, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 638;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 339, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 639;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 340, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 640;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 341, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 641;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 342, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 642;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 343, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 643;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 344, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 644;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 345, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 645;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 346, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 646;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 347, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 647;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 348, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 648;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 349, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 649;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 350, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 650;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 351, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 651;- 399 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 352, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 652;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 353, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 653;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 354, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 654;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 355, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 655;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 356, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 656;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 357, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 657;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 358, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 658;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 359, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 659;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 660;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 661;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 662;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 363, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 663;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 364, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 664;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 365, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 665;- 400 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENTthe sense strand comprises a nucleic acid sequence of SEQ ID NO: 366, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 666;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 367, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 667;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 368, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 668;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 369, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 669;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 370, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 670;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 371, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 671;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 372, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 672;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 673;the sense strand comprises a nucleic acid sequence of SEQ ID NO: 374, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 674; or the sense strand comprises a nucleic acid sequence of SEQ ID NO: 375, and the antisense strand comprises a nucleic acid sequence of SEQ ID NO: 675.

40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of any one of claims 1-39.

41. A kit comprising the composition of any one of claims 1 -39, or the pharmaceutical composition of claim 40.

42. A method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is characterized by dysregulation of the IFIH1 / MDA5 axis, the method comprising administering to the subject the composition of any one of claims 1-39, or the pharmaceutical composition of claim 40.- 401 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT43. The method of claim 42, wherein the disease or disorder is an immunological disease, an autoimmune disease, a type I interferonopathy, an inflammatory disorder, a cardiovascular disease, a pancreatic islet disorder, or a metabolic disease.

44. The method of claim 43, wherein the disease or disorder is type 1 diabetes, systemic lupus erythematosus, coronary artery disease, atherosclerosis, vascular inflammation, islet inflammation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, Aicardi-Goutieres syndrome, spondyloenchondrodysplasia, Sjogren's syndrome, or psoriasis.

45. The method of any one of claims 42-44, wherein the subject has a wild-type IFIH1 allele, a risk variant IFIH1 allele, or is heterozygous for a risk variant IFIH1 allele.

46. The method of claim 45, wherein the risk variant IFIH1 allele is rsl990760.

47. A method of reducing expression of a target gene in a cell, the method comprising contacting the cell with the composition of any one of claims 1-39, or the pharmaceutical composition of claim 40, wherein the target gene is IFIH1.

48. The method of claim 47, wherein the cell is a CD71 positive cell selected from an immune cell, a pancreatic beta cell, a pancreatic islet cell, a vascular smooth muscle cell, or a vascular endothelial cell.

49. The method of claim 48, wherein the immune cell is a dendritic cell, a B cell, a T cell, a monocyte, a macrophage, a peripheral blood mononuclear cell, or a splenocyte.

50. The method of any one of claims 47-49, wherein the reduction in expression of IFIH1 results in a reduction in IFIH1 mRNA of about 50% to about 99%.

51. The method of any one of claims 47-50, wherein the reduction in expression of IFIH1 results in a reduction in MDA5 protein levels of about 50% to about 99%.

52. A method of delivering an siRNA molecule to a CD71 expressing cell in a subject, the method comprising administering to the subject the composition of any one of claims 1-39, or the pharmaceutical composition of claim 40, wherein the siRNA molecule targets IFIH 1 and downregulates IFIH1 mRNA expression in the CD71 expressing cell.

53. The method of claim 52, wherein the CD71 expressing cell is an immune cell, a pancreatic beta cell, a pancreatic islet cell, a vascular smooth muscle cell, or a vascular endothelial cell.- 402 - TPTS / 200322635.1Attorney Docket No. ROO-037WO PATENT54. A method of reducing one or more cytokines in a subject in need thereof, the method comprising administering to the subject the composition of any one of claims 1-39, or the pharmaceutical composition of claim 40.

55. The method of claim 54, wherein the one or more cytokines comprises IFN-a, IFN-β, IFN-y, IL-6, TNF-a, IL-12, IP-10, RANTES, or any combination thereof.

56. The method of claim 54 or 55, wherein the reduction in one or more cytokines results in reduced interferon-stimulated gene expression, reduced type I interferon signaling, or reduced inflammation in CD71 positive cells comprising immune cells, pancreatic beta cells, vascular smooth muscle cells, or any combination thereof.

57. Use of the pharmaceutical composition of claim 40 in the preparation of a medicament for treating a disease or disorder characterized by dysregulation of the IFIH1 / MDA5 axis.

58. The use of claim 57, wherein the disease or disorder is an immunological disease, an autoimmune disease, a type I interferonopathy, a cardiovascular disease, a pancreatic islet disorder, or an inflammatory disorder.

59. The use of claim 58, wherein the disease or disorder is type 1 diabetes, systemic lupus erythematosus, coronary artery disease, atherosclerosis, vascular inflammation, islet inflammation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, Aicardi-Goutieres syndrome, spondyloenchondrodysplasia, Sjogren's syndrome, or psoriasis.

60. The use of any one of claims 57-59, wherein the medicament is for administration to a subject having a wild-type IFIH1 allele, a risk variant IFIH1 allele, or heterozygous for a risk variant IFIH1 allele.

61. The use of any one of claims 57-60, wherein the medicament reduces IFIH1 expression in CD71 positive cells selected from immune cells, pancreatic beta cells, vascular smooth muscle cells, pancreatic islet cells, or vascular endothelial cells.

62. The use of any one of claims 57-61, wherein the medicament reduces one or more cytokines selected from IFN-a, IFN-β, IFN-y, IL-6, TNF-a, IL-12, IP-10, RANTES, or any combination thereof, thereby reducing interferon-stimulated gene expression, type I interferon signaling, or inflammation.- 403 - TPTS / 200322635.1

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