Methods and compositions for treating pompe disease

Abstract

Provided for herein are methods and compositions for treating Pompe disease, including the delivery of oligonucleotides for treating Pompe disease.

Description

Attorney Docket No. ROO-039WO PATENT METHODS AND COMPOSITIONS FOR TREATING POMPE DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 642,236, filed May 3, 2024, 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 May 2, 2025, is named “ROO-039WO_SL.xml” and is 72,622 bytes in size. FIELD

[0003] The present embodiments relate to compositions comprising polypeptide- oligonucleotide conjugates, such as FN3 domain-siRNA conjugates, for treating Pompe disease and / or monitoring the effect, efficacy, or responsiveness to treatment of the same. BACKGROUND

[0004] Therapeutic nucleic acids include, e.g., small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides, ribozymes, plasmids, immune stimulating nucleic acids, antagomirs, antimirs, microRNA mimics, supermirs, U1 adaptors, and aptamers. siRNA or miRNA constructs can down-regulate intracellular levels of specific proteins through a process termed RNA interference (RNAi). Therapeutic applications of RNAi are extremely broad because, for example, an siRNA or a miRNA construct can be synthesized to have any nucleotide sequence directed against a target gene. siRNA constructs are known to be able to specifically down-regulate target proteins in both in vitro and in vivo models. In addition, siRNA-based products have been approved for treating a variety of diseases, such as hereditary transthyretin-mediated amyloidosis and acute hepatic porphyria, and still others are being evaluated in clinical trials.

[0005] However, two problems currently faced by siRNA constructs are their susceptibility to nuclease digestion in plasma and their limited ability to gain access to the intracellular compartment where they can bind the RISC (RNA-induced Silencing Complex) when administered systemically as the free siRNA or miRNA. Certain delivery systems, such as 1 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 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 to facilitate the cellular uptake of siRNAs but have not been successful in efficient and effective delivery to their intended targets in tissues other than the liver.

[0006] There remains a need for compositions and methods for delivering an siRNA to its intended cellular target. Pompe disease, also known as glycogen storage disease type II (GSD-II) or acid maltase deficiency, is an inherited disorder of glycogen metabolism resulting from defects in the activity of lysosomal acid α-glucosidase (GAA), a glycogen degrading enzyme. In its most severe form, the disease is characterized by massive cardiomegaly, macroglossia, progressive muscle weakness and marked hypotonia in early infancy. Most infantile patients are diagnosed between 3-6 months of age and die before 1 year of age.

[0007] The development of a screening assay for Pompe disease or other glycogen storage diseases would be particularly beneficial in infantile forms of the disease, where patients typically survive for merely months after diagnosis. Early prognosis and treatment of neonates or infants with Pompe disease or other glycogen storage diseases may improve the prognosis for these patients. Moreover, a method of monitoring therapy may improve the efficacy of treatment and the prognosis for patients suffering from Pompe disease or other glycogen storage diseases. The present embodiments fulfill these needs as well as others. SUMMARY

[0008] In some embodiments, provided herein are methods of treating glycogen storage diseases. In some embodiments, provided herein are methods of treating Pompe disease in a subject in need thereof, comprising administering a composition comprising: an FN3 polypeptide that binds to CD71; and an oligonucleotide, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1, and wherein the oligonucleotide is administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg.

[0009] In some embodiments, provided herein are methods of treating Pompe disease in a subject in need thereof, comprising administering a composition comprising: an FN3 polypeptide comprising an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 5 or SEQ ID NO: 6; and an oligonucleotide comprising: a sense strand comprising the oligonucleotide having the nucleic 2 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or 100% identical to SEQ ID NO: 8, or a modified version thereof; and an antisense strand comprising the oligonucleotide having the nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 9, or a modified version thereof, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1, and wherein the oligonucleotide is administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg.

[0010] In some embodiments, provided herein are methods of treating Pompe disease in a subject in need thereof, comprising administering a composition comprising: an FN3 polypeptide comprising an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 5 or SEQ ID NO: 6; and an siRNA oligonucleotide comprising: a sense strand comprises a modified oligonucleotide having the nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or 100% identical to SEQ ID NO: 10; and an antisense strand comprises a modified oligonucleotide having the nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 11, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1, and wherein the composition is administered at a dose of about 1 mg / kg to about 60 mg / kg, and comprises the siRNA administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg, respectively. 3 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0011] In some embodiments, provided herein are methods of treating Pompe disease in a subject in need thereof, comprising administering a composition comprising: an FN3 polypeptide comprising an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 5 or SEQ ID NO: 6; and an siRNA oligonucleotide comprising: a sense strand modified oligonucleotide comprises the nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or 100% identical to SEQ ID NO: 12; and an antisense modified oligonucleotide has the nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 13, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1 selected from the group consisting of: 6), wherein L1(PEG) bond to the(iii) or Aminohexyl linker-bond to the siRNA; or 4 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT ,and and comprises the siRNA administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg, respectively. BRIEF DESCRIPTION OF DRAWINGS

[0012] FIGs.1A and 1B show dose and time dependent reduction of both GYS1 mRNA and protein observed in single and multi-dose arms of healthy volunteer study. DETAILED DESCRIPTION Definitions

[0013] Provided herein are compositions comprising a FN3 polypeptide linked to an oligonucleotide for treatment of Pompe disease. It is to be understood that the embodiments described herein are not limited to particular compositions and experimental conditions disclosed, as such formulations, compositions, and experimental conditions may vary. It is also to be understood that the terminology used herein is only for the purpose of describing particular embodiments, and it is not intended to be limiting.

[0014] Furthermore, the formulations, compositions, and experimental conditions described herein, unless otherwise indicated, use conventional molecular and cellular biological and immunological techniques known within the skill of the art. Such techniques are well known to the skilled artisan and are explained fully in the literature. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2008), including all supplements, Molecular Cloning: A Laboratory Manual (Fourth Edition) by MR Green and J. Sambrook and Harlow et al., Antibodies: A Laboratory Manual, Chapter 14, Cold Spring Harbor Laboratory, Cold Spring Harbor (2013, 2nd edition).

[0015] Unless defined otherwise, all technical and scientific terms have the same meaning as it is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belong. Certain terms are discussed below, or elsewhere in the specification, to 5 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT provide additional guidance to the practitioner in describing the methods of the disclosure and how to use them. Moreover, it will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in the specification, including examples of any terms discussed herein, is illustrative only, and in no way limits the scope and meaning of the disclosure or any exemplified term. Likewise, the disclosure is not limited to its preferred embodiments.

[0016] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.

[0017] That the disclosure may be more readily understood, select terms are defined.

[0018] The articles “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0019] As used herein, the adverbs “about” or “approximately” mean that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ± 5% and remain within the scope of the disclosed embodiments. Thus, about 100 means 95 to 105.

[0020] As used herein, the irregular verb “has” and its conjugates, and the verbs “comprise,” “include,” “contain” and their conjugates, mean “including but not limited to.” As used herein, the term “including but not limited to” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. While various compositions, and methods are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and devices can also “consist essentially of” or “consist of” the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups.

[0021] “Polynucleotide” refers to a synthetic molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. Examples of polynucleotides include, but are not limited to, a gene, a messenger RNA (mRNA), a viral RNA, or a complementary DNA (cDNA). 6 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0022] “Polypeptide” or “protein” refers to a molecule that comprises at least two amino acid residues linked by a peptide bond to form a polypeptide. A small polypeptide of less than about 50 amino acids may be referred to as a “peptide.”

[0023] “Encode” or “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. In a double-stranded polynucleotide having a coding strand (identical to an mRNA sequence and typically the strand provided in sequence listings) and a non-coding strand (used as a template for transcription of a gene or a cDNA), both strands can be referred to as encoding the protein or other product of that gene or cDNA.

[0024] “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, virus, animal, plant, and reconstituted biological systems utilizing biological components capable of duplicating a vector. The polynucleotide comprising a vector may be DNA or RNA molecules or a hybrid of these.

[0025] “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.

[0026] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a polypeptide 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.

[0027] “Stability” or “conformational 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 7 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT functional activities, for example, binding to a predetermined antigen such as human CD71 protein.

[0028] “Specifically binds” or “specific binding” refers to the ability of a binding domain, such as an FN3 domain, to bind to its target, such as CD71, with a dissociation constant (KD) of about 1x10-6M or less, for example about 1x10-7M or less, about 1x10-8M or less, about 1x10-9M or less, about 1x10-10M or less, about 1x10-11M or less, about 1x10-12M or less, or about 1x10-13M or less. Alternatively, “specific binding” refers to the ability of an FN3 domain to bind to its target (e.g., CD71) at least 5-fold above a negative control in standard solution ELISA assay. Specific binding can also be demonstrated using a proteome array. In some embodiments, a negative control is an FN3 domain that does not bind CD71. In some embodiment, 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).

[0029] “Antigen” refers to the binding partner of a binding domain, such as an FN3 domain. Included within the definition of “antigen” is a protein-encoding nucleic acid. Examples of antigens include, but are not limited to, CD71.

[0030] “Epitope” or “antigen-binding site” refers to that portion of any molecule capable of being recognized by and bound by a binding domain, at one or more antigen-binding regions of the binding domain. An epitope usually consists of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and has specific three-dimensional structural characteristics and specific charge characteristics. Examples of epitopes include, but are not limited to, the amino acid residues described herein that form CD71 epitopes.

[0031] “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.

[0032] Reference in the present disclosure may be made to an FN3 domain, which can be used interchangeably with FN3 polypeptide or FN3 protein. “Fibronectin type III domain” or “FN3 domain” or “Centyrin” refers to a polypeptide domain occurring frequently in proteins including 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 8 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT tenascin C, the 15 different FN3 domains present in human fibronectin (FN), and non-natural synthetic FN3 domains as described in, for example, U.S. Patent 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). 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. Conjugates

[0033] In some embodiments, an FN3 polypeptide is provided. In some embodiments, the FN3 polypeptide is referred to as “F1”. In some embodiments, the FN3 polypeptide binds CD71. In some embodiments, the FN3 polypeptide specifically binds CD71.

[0034] In some embodiments, the FN3 polypeptide binds CD71 and is based on the Tencon sequence of SEQ ID NO: 1: LPAPKNLVVSEVTEDSLRLSWTAPDAAFDSFLIQYQESEKVGEAINLTVPGS ERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAEFTT (SEQ ID NO: 1); or on Tencon 27 sequence (SEQ ID NO: 27): LPAPKNLVVSRVTEDSARLSWTAPDAAFDSFLIQYQESEKVGEAIVLTVPGS ERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAIFTT (SEQ ID NO: 27).

[0035] In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 5: MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFYIAYAEPRPDGEAILLQVPGSERSY DLTGLKPGTEYSVLIHGVKGGLLSSPLTAIFTT (SEQ ID NO: 5).

[0036] In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises 9 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT an amino acid sequence that is at least 96% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 5. In some embodiments, the FN3 polypeptide comprises the amino acid sequence of SEQ ID NO: 5.

[0037] In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 6: MLPAPKNLVVSRVTEDSARLSWTAPDAAFDSFYIAYAEPRPDGEAILLQVPGSCRSY DLTGLKPGTEYSVLIHGVKGGLLSSPLTAIFTT (SEQ ID NO: 6).

[0038] In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 6. In some embodiments, the FN3 polypeptide comprises the amino acid sequence of SEQ ID NO: 6.

[0039] In some embodiments, the FN3 polypeptide comprises an amino acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 5 or SEQ ID NO: 6. 10 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0040] In some embodiments, the FN3 polypeptide binds CD71. In some embodiments, the FN3 polypeptide comprise a polypeptide (F1) that binds CD71. In some embodiments, the FN3 polypeptide comprise a polypeptide (F1) that binds CD71 of SEQ ID NO: 2. In some embodiments, the FN3 polypeptide comprise a polypeptide (F1) that binds the extracellular domain of CD71 of SEQ ID NO: 3. In some embodiments, the polypeptide (F1) comprises a FN3 domain that binds to CD71. In some embodiments, the polypeptide (F1) comprises a sequence of SEQ ID NO: 5 or SEQ ID NO: 6.

[0041] In some embodiments, the FN3 polypeptide that binds CD71 comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the FN3 polypeptide that binds CD71 comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, FN3 polypeptide that binds CD71 comprises SEQ ID NO: 5, wherein SEQ ID NO: 5 further comprises a cysteine 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 SEQ ID NO: 5. In some embodiments, the cysteine is located at a position that corresponds to residue 6, 54, or 88 of SEQ ID NO: 5.

[0042] In some embodiments, the FN3 polypeptide comprises two FN3 polypeptides connected by a linker, for example, F1-F2. The linker can be a flexible linker. The linker between F1 and F2 can be a short peptide sequence, including but not limited to those described herein. For example, the linker can be a G / S or G / A linker and the like. As provided herein, the linker can be, for example, (GS)2 (SEQ ID NO: 14), (GGGS)2 (SEQ ID NO: 15), (GGGGS)5 (SEQ ID NO: 16), (AP)2 (SEQ ID NO: 17), (AP)5 (SEQ ID NO: 18), (AP)10 (SEQ ID NO: 19), (AP)20 (SEQ ID NO: 20), A(EAAAK)5AAA (SEQ ID NO: 21), or (EAAAK)1-5 (SEQ ID NO: 22, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 23, and SEQ ID NO: 30, respectively). These are non-limiting examples and other linkers can also be used. The number of GGGGS (SEQ ID NO: 31) or GGGGA (SEQ ID NO: 32) repeats can also be 1, 2, 3, 4, or 5. In some embodiments, the linker comprises one or more GGGGS (SEQ ID NO: 31) repeats and one or more GGGGA (SEQ ID NO: 32) repeats. In some embodiments, the linker comprises EAAAKEAAAKEAAAKEAAAK (SEQ ID NO: 23), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 24), APAPAPAPAP (SEQ ID NO: 25), or EAAAK (SEQ ID NO: 26).

[0043] In some embodiments, the FN3 polypeptide is linked to an oligonucleotide molecule. In some embodiments, the FN3 polypeptide linked to the oligonucleotide is referred to as a macromolecule. 11 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0044] In some embodiments, an oligonucleotide is provided. In some embodiments, the oligonucleotide is linked to the FN3 polypeptide. In some embodiments, the oligonucleotide can be, for example, an siRNA molecule as provided herein.

[0045] In some embodiments, the oligonucleotide is a double-stranded RNAi (dsRNA) agent capable of inhibiting expression of GYS1. In some embodiments, the oligonucleotide is a dsRNA agent capable of hybridizing to a target nucleic acid sequence (e.g., an siRNA molecule). In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA.

[0046] In some embodiments, the full length nucleic acid sequence of human GYS1 mRNA is SEQ ID NO: 7, provided as NCBI Reference Sequence: NM_001161587.2, reproduced below: AGTGACGCTGCGGCCTCCTTCTGCCTAGGTCCCAACGCTTCGGGGCAGGGGT GCGGTCTTGCAATAGGAAGCCGAGCGTCTTGCAAGCTTCCCGTCGGGCACCA GCTACTCGGCCCCGCACCCTACCTGGTGCATTCCCTAGACACCTCCGGGGTC CCTACCTGGAGATCCCCGGAGCCCCCCTTCCTGCGCCAGCCATGCCTTTAAA CCGCACTTTGTCCATGTCCTCACTGCCAGGACTGGAGGACTGGGAGGATGAA TTCGACCTGGAGAACGCAGTGCTCTTCGAAGTGGCCTGGGAGGTGGCTAACA AGGTGGGTGGCATCTACACGGTGCTGCAGACGAAGGCGAAGGTGACAGGGGA CGAATGGGGCGACAACTACTTCCTGGTGGGGCCGTACACGGAGCAGGGCGTG AGGACCCAGGTGGAACTGCTGGAGGCCCCCACCCCGGCCCTGAAGAGGACAC TGGATTCCATGAACAGCAAGGGCTGCAAGTTCCTGGCACAGAGTGAGGAGAA GCCACATGTGGTTGCTCACTTCCATGAGTGGTTGGCAGGCGTTGGACTCTGC CTGTGTCGTGCCCGGCGACTGCCTGTAGCAACCATCTTCACCACCCATGCCA CGCTGCTGGGGCGCTACCTGTGTGCCGGTGCCGTGGACTTCTACAACAACCT GGAGAACTTCAACGTGGACAAGGAAGCAGGGGAGAGGCAGATCTACCACCGA TACTGCATGGAAAGGGCGGCAGCCCACTGCGCTCACGTCTTCACTACTGTGT CCCAGATCACCGCCATCGAGGCACAGCACTTGCTCAAGAGGAAACCAGATAT TGTGACCCCCAATGGGCTGAATGTGAAGAAGTTTTCTGCCATGCATGAGTTC CAGAACCTCCATGCTCAGAGCAAGGCTCGAATCCAGGAGTTTGTGCGGGGCC ATTTTTATGGGCATCTGGACTTCAACTTGGACAAGACCTTATACTTCTTTAT CGCCGGCCGCTATGAGTTCTCCAACAAGGGTGCTGACGTCTTCCTGGAGGCA TTGGCTCGGCTCAACTATCTGCTCAGAGTGAACGGCAGCGAGCAGACAGTGG TTGCCTTCTTCATCATGCCAGCGCGGACCAACAATTTCAACGTGGAAACCCT CAAAGGCCAAGCTGTGCGCAAACAGCTTTGGGACACGGCCAACACGGTGAAG GAAAAGTTCGGGAGGAAGCTTTATGAATCCTTACTGGTTGGGAGCCTTCCCG ACATGAACAAGATGCTGGATAAGGAAGACTTCACTATGATGAAGAGAGCCAT CTTTGCAACGCAGCGGCAGTCTTTCCCCCCTGTGTGCACCCACAATATGCTG GATGACTCCTCAGACCCCATCCTGACCACCATCCGCCGAATCGGCCTCTTCA ATAGCAGTGCCGACAGGGTGAAGGTGATTTTCCACCCGGAGTTCCTCTCCTC CACAAGCCCCCTGCTCCCTGTGGACTATGAGGAGTTTGTCCGTGGCTGTCAC CTTGGAGTCTTCCCCTCCTACTATGAGCCTTGGGGCTACACACCGGCTGAGT GCACGGTTATGGGAATCCCCAGTATCTCCACCAATCTCTCCGGCTTCGGCTG CTTCATGGAGGAACACATCGCAGACCCCTCAGCTTACGGTATCTACATTCTT GACCGGCGGTTCCGCAGCCTGGATGATTCCTGCTCGCAGCTCACCTCCTTCC TCTACAGTTTCTGTCAGCAGAGCCGGCGGCAGCGTATCATCCAGCGGAACCG 12 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT CACGGAGCGCCTCTCCGACCTTCTGGACTGGAAATACCTAGGCCGGTACTAT ATGTCTGCGCGCCACATGGCGCTGTCCAAGGCCTTTCCAGAGCACTTCACCT ACGAGCCCAACGAGGCGGATGCGGCCCAGGGGTACCGCTACCCACGGCCAGC CTCGGTGCCACCGTCGCCCTCGCTGTCACGACACTCCAGCCCGCACCAGAGT GAGGACGAGGAGGATCCCCGGAACGGGCCGCTGGAGGAAGACGGCGAGCGCT ACGATGAGGACGAGGAGGCCGCCAAGGACCGGCGCAACATCCGTGCACCAGA GTGGCCGCGCCGAGCGTCCTGCACCTCCTCCACCAGCGGCAGCAAGCGCAAC TCTGTGGACACGGCCACCTCCAGCTCACTCAGCACCCCGAGCGAGCCCCTCA GCCCCACCAGCTCCCTGGGCGAGGAGCGTAACTAAGTCCGCCCCACCACACT CCCCGCCTGTCCTGCCTCTCTGCTCCAGAGAGAGGATGCAGAGGGGTGCTGC TCCTAAACCCCCGCTCCAGATCTGCACTGGGTGTGGCCCCGCAGTGCCCCCA CCCAGTCCGCCAAACACTCCACCCCCTCCAGCTCCAGTTTCCAAGTTCCTGC ACTCCAGAATCCACAAAGCCGTGCCTTTCTCTGGCTCCAGAATATGCATAAT CAGCGCCCTGGAGTCCCCTGGGCCTGGACCGCTTCCCAGAGGCCAGGAATCT GCCATTACTCTGCGGTGGTGCCAGAGGTTTTAGGAAACCTGGCATGGTGCTT TCAGGTCTGGGGCTTTTAGAGCCCCCCGTGTGGCTTACAAATTCTACAGCAT ACAGAGCAGGCCACGCTCAGGCCCGGCATGCGGGCCACCAAGTTCTGGAAAC CACGTGGTGTCCCTGCGAATGGGGCGATCAAGTCCAGAGCCGGGGCACTTTC AGAGTTTGAAGGTAACTGAGAGCAGATGGTCCTCCATTTCAACTCCAGAAGT GGGGCTCTGGGAGGGATGTTCTAGCCCTCCCTGGCATGTCAGAGCCAGGCTC TGCCTGGAGGATCCCTCCATCCGGCTCCTGTCATCCCCTACACTTTGGCCAA GCAAGAGGTGGTAGAACCACTTGGCTGCTCATTCCTTCTGGAGGACACACAG TCTCAGTCCAGATGCCTTCCTGTCTTTCTGGCCCTTTCTGGACCAGATCCTA CTCTTCCTTTCTAAATCTGAGATCTCCCTCCAGGGAATCCGCCTGCAGAGGA CAGAGCTGGCTGTCTTCCCCCACCCCTAACCTGGCTTATTCCCAACTGCTCT GCCCACTGTGAAACCACTAGGTTCTAGGTCCTGGCTTCTAGATCTGGAACCT TACCACGTTACTGCATACTGATCCCTTTCCCATGATCCAGAACTGAGGTCAC TGGGTTCTAGAACCCCCACATTTACCTCGAGGCTCTTCCATCCCCAAACTGT GCCCTGCCTTCAGCTTTGGTGAAAGGGAGGGCCCCTCATGTGTGCTGTGCTG TGTCTGCACCGCTTGGTTTGCAGTTGAGAGGGGAGGGCAGGAGGGGTGTGAT TGGAGTGTGTCCGGAGATGAGATGAAAAAAATACATCTATATTTAAGAA (SEQ ID NO: 7).

[0047] In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 90% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 91% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a 13 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT nucleic acid sequence that is at least 92% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 93% identical to that of SEQ ID NO: 1. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 94% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 95% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 96% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 97% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 98 % identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is at least 99% identical to that of SEQ ID NO: 7. In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA, wherein the GYS1 mRNA comprises a nucleic acid sequence that is 100% identical to that of SEQ ID NO: 7.

[0048] 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 nucleic acid sequence of GYS1 mRNA.

[0049] In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 40% complementary, at least 50% complementary, at least 55% complementary, at least 60% complementary, at least 65% complementary, at least 70% complementary, at least 75% complementary, at least 80% complementary, at least 85% complementary, at least 90% complementary, at least 95% complementary, at least 98% complementary, at least 99% complementary, at least 99.5% complementary, or 100% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 40% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid 14 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT sequence that is at least 50% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% complementary to the target nucleic acid sequence of a GYS1 mRNA. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% complementary to the target nucleic acid sequence of a GYS1 mRNA.

[0050] In some embodiments, the oligonucleotide is capable of hybridizing to a target nucleic acid sequence of a GYS1 mRNA that is about 10 to about 50 nucleotides in length.

[0051] In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 40% complementary, at least 50% complementary, at least 55% complementary, at least 60% complementary, at least 65% complementary, at least 70% complementary, at least 75% complementary, at least 80% complementary, at least 85% complementary, at least 90% complementary, at least 95% complementary, at least 98% complementary, at least 99% complementary, at least 99.5% complementary, or 100% complementary to the target nucleic acid sequence of a GYS1 mRNA that is about 10 to about 50 nucleotides in length. 15 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0052] In some embodiments, the target nucleic acid sequence of GYS1 mRNA 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 GYS1, in which the first nucleotide of the target sequence starts at any nucleotide in GYS1 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 GYS1 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 GYS1 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- nal 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- nal 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.

[0053] In some embodiments, the 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.

[0054] In some embodiments, the oligonucleotide molecule is an siRNA molecule comprising a sense strand. In some embodiments, the oligonucleotide molecule is an siRNA molecule comprising an antisense strand. In some embodiments, the oligonucleotide molecule is an siRNA molecule comprising a sense strand and an antisense strand.

[0055] In some embodiments, the oligonucleotide is an siRNA molecule. In some embodiments, the siRNA is a double-stranded RNAi (dsRNA) molecule capable of inhibiting 16 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT the expression of a target gene. The dsRNA molecule comprises a sense strand (passenger strand) and an antisense strand (guide strand). In some embodiments, each strand of the dsRNA molecule can range from 10-50 nucleotides in length. For example, each strand can be from 12-45 nucleotides in length, 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, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length.

[0056] 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 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotide pairs in length.

[0057] 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 can be other 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.

[0058] In some embodiments, the sense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, at least 99.5% identical, or 100% identical to SEQ ID NO: 8: UUACGGUAUCUACAUUCUA (SEQ ID NO: 8) 17 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% identical to SEQ ID NO: 8, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% identical to SEQ ID NO: 8, or a modified version thereof.

[0059] In some embodiments, the antisense strand comprises an oligonucleotide comprising the nucleic acid sequence of SEQ ID NO: 8, or a modified version thereof.

[0060] In some embodiments, the antisense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: UAGAAUGUAGAUACCGUAAUU (SEQ ID NO: 9) or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50% identical to SEQ ID NO: 9, or a modified version thereof. 18 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% identical to SEQ ID NO: 9, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% identical to SEQ ID NO: 9, or a modified version thereof.

[0061] In some embodiments, the oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 9, or a modified version thereof.

[0062] In some embodiments, the oligonucleotide, i.e. sense strand or antisense strand, does not contain any nucleotides comprising a modification.

[0063] In some embodiments, the oligonucleotide, i.e. sense strand or antisense strand, comprises a nucleotide comprising a modification selected from the group consisting of: a 2’- O-methyl modification, 2’-deoxy modification, 2’-fluoro modification, a 2’-deoxy 2’-fluoro modification, a 2’-O methoxyethyl (2’ O MOE) modification, a 2’-O-aminopropyl modification, a 2’-O-aminopropyl (2’ O AP) modification, a 2’-O-dimethylaminoethyl (2’-O- DMAOE) modification, a 2’-O-dimethylaminopropyl (2’-O-DMAP) modification, a 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE) modification, a 2’-O-N-methylacetamido (2’- O-NMA) modification, a locked nucleic acid (LNA) modification, a 2’-O,4’-C Ethylene bridge nucleic acid (ENA) modification, a peptide nucleic acid (PNA) modification, a hexitol 19 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT nucleic acid modification, a morpholino modification, a phosphorothioate (PS) modification, a phosphorodithioate modification, a phosphonate modification, a vinyl phosphonate modification, 2’-O-methyl vinyl phosphonate modification, a thiolphosphonate modification, a methylphosphonate modification, a phosphoramidate modification, a mesyl phosphoramidate modification, a methyl phosphoramidate modification, and a 2’-fluoro N3 P5’ phosphoramidite modification, or a combination thereof.

[0064] In some embodiments, the oligonucleotide molecule, i.e. sense strand or antisense strand, described herein comprises 2’-5’ internucleotide linkages. In some embodiments, 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.

[0065] In some embodiments, the oligonucleotide comprises a synthetic nucleotide analogue.

[0066] In some embodiments, one or more of the synthetic nucleotide analogues described herein are resistant toward nucleases such as for example ribonuclease such as RNase H, deoxyribonuclease such as DNase, or exonuclease such as 5’-3’ exonuclease and 3’-5’ exonuclease when compared to natural polynucleic acid molecules and endonucleases. In some embodiments, 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- 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 combinations thereof are resistant toward nucleases such as for example ribonuclease such as RNase H, deoxyribonuclease such as DNase, or exonuclease such as 5’- 3’ exonuclease and 3’-5’ exonuclease. In some embodiments, 2’-O-methyl modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’O-methoxyethyl (2’-O-MOE) modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O-aminopropyl 20 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’- deoxy modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-deoxy-2’-fluoro modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O-aminopropyl (2’-O-AP) modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O-dimethylaminoethyl (2’-O- DMAOE) modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O- dimethylaminopropyl (2’- O-DMAP) modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE) modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, 2’-O-N-methylacetamido (2’-O-NMA) modified oligonucleotide molecule is nuclease resistance (e.g,, RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, LNA modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, ENA modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, HNA modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, morpholinos is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, PNA modified oligonucleotide molecule is resistant to nucleases (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, methylphosphonate nucleotides modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, thiolphosphonate nucleotides modified oligonucleotide molecule is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, oligonucleotide molecule comprising 2’-fluoro N3-P5’-phosphoramidites is nuclease resistance (e.g., RNase H, DNase, 5’-3’ exonuclease or 3’-5’ exonuclease resistance). In some embodiments, the 5’ conjugates described herein inhibit 5’-3’ exonucleolytic cleavage. In some embodiments, the 3’ conjugates described herein inhibit 3’-5’ exonucleolytic cleavage. 21 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0067] 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- dimethylaminoethyloxyethyl (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 an equivalent natural polynucleic acid molecule. In some embodiments, 2’-O-methyl modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, 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 embodiments, 2’-O-aminopropyl modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, 2’- deoxy modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, LNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target 22 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT relative to an equivalent natural polynucleic acid molecule. In some embodiments, ENA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, PNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, HNA modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, morpholino modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, methylphosphonate nucleotides modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, thiolphosphonate nucleotides modified oligonucleotide molecule has increased binding affinity toward their mRNA target relative to an equivalent natural polynucleic acid molecule. In some embodiments, oligonucleotide molecule comprising 2’-fluoro N3-P5’-phosphoramidites has increased binding affinity toward their 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.

[0068] In some embodiments, the 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 embodiments, the oligonucleotide molecule comprises L- nucleotide. In some embodiments, the oligonucleotide molecule comprises D-nucleotides. In some instance, the 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, the oligonucleotide molecule composition comprises less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or less of a racemic mixture.

[0069] In some embodiments, the oligonucleotide molecule described herein is further modified to include an aptamer conjugating moiety. In some embodiments, the aptamer conjugating moiety is a DNA aptamer conjugating moiety. In some embodiments, 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 epitopes for attaching to circulating antibodies.

[0070] In additional embodiments, the oligonucleotide molecule described herein is modified to increase its stability. In some embodiment, the oligonucleotide molecule is RNA (e.g., 23 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT siRNA). In some embodiments, 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 morpholinos, PNAs, HNA, methylphosphonate nucleotides, thiolphosphonate nucleotides, and / or 2’-fluoro N3-P5’- phosphoramidites to increase its stability. In some embodiments, the oligonucleotide molecule is a chirally pure (or stereo pure) oligonucleotide molecule. In some embodiments, 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.

[0071] In some embodiments, the sense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 10: [mU][*mU][*fA][mC][mG][mG][fU][fA][fU][mC][mU][fA][mC][mA ][mU][mU][fC][mU][mA] (SEQ ID NO: 10), wherein N = any nucleotide base (set off by brackets), mN = 2’-O-methyl-modified nucleotides, fN= 2’-F-modified nucleotides, and * = phosphorothioate. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the 24 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT oligonucleotide comprises a nucleic acid sequence that is at least 75% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% identical to SEQ ID NO: 10, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% identical to SEQ ID NO: 10, or a modified version thereof.

[0072] In some embodiments, the oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 10, or a modified version thereof.

[0073] In some embodiments, the antisense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 11: [mU][*fA][*mG][mA][mA][mU][mG][mU][mA][mG][mA][mU][mA][fC ][mC][mG][mU][mA][mA][*mU][*mU] (SEQ ID NO: 11), wherein N = any nucleotide base (set off by brackets), mN = 2’-O-methyl-modified nucleotides, fN= 2’-F-modified nucleotides, and * = phosphorothioate. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65 % identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% 25 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% identical to SEQ ID NO: 11, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% identical to SEQ ID NO: 11, or a modified version thereof.

[0074] In some embodiments, the oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 11, or a modified version thereof.

[0075] In some embodiments, the oligonucleotide, i.e. sense strand or antisense strand, further comprises a covalently attached linker molecule (L1). In some embodiments, the covalently attached linker molecule on the sense strand (L1) is also covalently attached to the FN3 polypeptide. In some embodiments, the covalently attached linker molecule on the antisense strand (L1) is also covalently attached to the FN3 polypeptide. In some embodiments, the sense strand is connected to the antisense strand via a linker molecule and the linker molecule is covalently connected to the FN3 polypeptide. In some embodiments, the linker molecule is a polynucleotide linker. In some embodiments, the linker molecule is a non-nucleotide linker.

[0076] In some embodiments, the sense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 12: [mU][*mU][*fA][mC][mG][mG][fU][fA][fU][mC][mU][fA][mC][mA ][mU][mU][fC][mU][mA]-L1 (SEQ ID NO: 12), 26 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT wherein N = any nucleotide base (set off by brackets), mN = 2’-O-methyl-modified nucleotides, fN = 2’-F-modified nucleotides, * = phosphorothioate, and L1 = linker. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5% identical to SEQ ID NO: 12, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100% identical to SEQ ID NO: 12, or a modified version thereof.

[0077] In some embodiments, the oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 12, or a modified version thereof.

[0078] In some embodiments, the antisense strand comprises the oligonucleotide comprising a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 13: 27 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT [VP][mU][*fA][*mG][mA][mA][mU][mG][mU][mA][mG][mA][mU][mA ][fC][mC][mG][mU][mA][mA][*mU][*mU] (SEQ ID NO: 13), wherein N = any nucleotide base (set off by brackets), mN = 2’-O-methyl-modified nucleotides, fN= 2’-F-modified nucleotides, * = phosphorothioate, and VP = vinyl phosphonate. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 50 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 55 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 60 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 65 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 70 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 75 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 80 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 85 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 90 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 95 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 98 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is at least 99.5 % identical to SEQ ID NO: 13, or a modified version thereof. In some embodiments, the oligonucleotide comprises a nucleic acid sequence that is 100 % identical to SEQ ID NO: 13, or a modified version thereof.

[0079] In some embodiments, the oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 13, or a modified version thereof.

[0080] Although certain siRNA sequences are illustrated herein with certain modified nucleobases, the sequences without such modifications are also provided herein. That is, the sequence can comprise the sequences provided herein without any modifications. The unmodified siRNA sequences can still comprise, in some embodiments, a linker at the 5’-end of the of the sense strand of the dsRNA. In some embodiments, the nucleic acid molecules 28 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT can be modified to include a vinyl phosphonate at the 5’-end of the of the anti-sense strand of the dsRNA. In some embodiments, the nucleic acid molecules can be modified to include a linker at the 3’-end of the of the sense strand of the dsRNA. In some embodiments, the nucleic acid molecules can be modified to include a vinyl phosphonate at the 3’-end of the of the antisense strand of the dsRNA. The linker can be as provided herein.

[0081] In some embodiments, the siRNA molecule is linked to a protein, such as an FN3 domain (F1). The siRNA can be linked to multiple FN3 domains (F2, F3, etc.) that bind to the same target protein or different target proteins. In some embodiments, the linker is attached to the sense strand, which is used to facilitate the linkage of the sense strand to the FN3 domain.

[0082] In some embodiments, the oligonucleotide molecule comprises a sense strand and an antisense strand, wherein the sense strand includes a terminal cap moiety at the 5’-end, the 3’- end, or both of the 5’-end and 3’-end of the sense strand. In other embodiments, the terminal cap moiety is an inverted deoxy abasic moiety.

[0083] In some embodiments, the 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.

[0084] In some embodiments, the 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 29 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 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.

[0085] In some embodiments, the 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 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 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.

[0086] In some embodiments, the 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 30 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 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 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, 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.

[0087] In some embodiments, the 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, 31 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 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.

[0088] In some embodiments, the 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 some embodiments, the 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, the 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 embodiments, the phosphate backbone modification is a phosphorothioate. In some embodiments, the phosphate backbone modification is a phosphorodithioate. In some embodiments, the phosphate backbone modification is a phosphonate. In some embodiments, the phosphate backbone modification is a phosphoramidate. In some embodiments, 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.

[0089] In some embodiments, the oligonucleotide molecule is a dsRNA molecule that mediates RNAi activity in a cell or reconstituted in vitro system. In some embodiments, the cell is a tumor cell, a liver cell, a muscle cell, an immune cell, a dendritic cell, a heart cell, or a cell of the central nervous system. 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. 32 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0090] In some embodiments, the 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 purine 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.

[0091] In some embodiments, the oligonucleotide molecule comprises a vinyl phosphonate modification on the sense strand. In some embodiments, the oligonucleotide molecule comprises a vinyl phosphonate modification on the antisense strand. In some embodiments, the oligonucleotide molecule comprises a vinyl phosphonate modification on the sense strand or the antisense strand. In some embodiments, the vinyl phosphonate modification is on the 5’-end or the 3’-end of the sense strand or the antisense strand. In some embodiments, the vinyl phosphonate modification is on the 5’-end of the sense strand. In some embodiments, the vinyl phosphonate modification is on the 5’-end of the antisense strand. In some embodiments, the vinyl phosphonate modification is on the 3’-end of the sense strand. In some embodiments, the vinyl phosphonate modification is on the 3’-end of the antisense strand.

[0092] In some embodiments, the oligonucleotide molecule comprises a sense strand and antisense strand, wherein pyrimidine nucleotides in the sense strand comprises 2’-O-methyl pyrimidine nucleotides and purine nucleotides in the sense strand comprise 2’-deoxy purine nucleotides.

[0093] In some embodiments, the oligonucleotide molecule comprises a sense strand and antisense strand, wherein pyrimidine nucleotides present in the sense strand comprise 2’- 33 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT deoxy-2’-fluoro pyrimidine nucleotides and wherein purine nucleotides present in the sense strand comprise 2’-deoxy purine nucleotides.

[0094] In some embodiments, the 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.

[0095] In some embodiments, the 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.

[0096] In some embodiments, the oligonucleotide molecule comprises a sense strand and antisense strand, and at least one of the sense strand and antisense strand 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 the 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.

[0097] In some embodiments, the 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 34 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 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- methyl modified nucleotide located at the 5’-end of the sense strand and / or the antisense strand is a pyrimidine nucleotide.

[0098] In some embodiments, the 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.

[0099] When connected to the oligonucleotide molecule, such as an siRNA, the structures can be represented by the following formulas:Attorney Docket No. ROO-039WO PATENT . (L1) is covalently attached to the5’-end or the 3’-end of the sense strand or the antisense strand.

[0101] In some embodiments, the linker molecule (L1) is covalently attached to the 3’-end of the modified sense strand; and the modified sense strand has a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 12.

[0102] In some embodiments, the linker molecule (L1) is covalently attached to the 3’-end of the modified sense strand; and the modified antisense strand has a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 13.

[0103] In some embodiments, the linker molecule (L1) is covalently attached to the 3’ end of the modified sense strand; the modified sense strand has a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 12; and the modified antisense strand has a nucleic acid sequence that is at least 50% identical, at least 55% identical, at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to that of SEQ ID NO: 13. 36 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0104] In some embodiments, the modified sense strand has a nucleic acid sequence of SEQ ID NO: 12. In some embodiments, the modified antisense strand has a nucleic acid sequence of SEQ ID NO: 13. In some embodiments, the modified sense strand has a nucleic acid sequence of SEQ ID NO: 12; and the modified antisense strand has a nucleic acid sequence of SEQ ID NO: 13.

[0105] In some embodiments, the FN3 polypeptide (F1) is linked to the olionucleotide molecule, such as an siRNA, through a linker molecule (L1), having the formula of siRNA- L1-F1. In some embodiments, the siRNA-L1- F1 has a formula of:

[0106] In some embodiments, a compound having a formula of Formula VI (top) or Formula VII (bottom):Attorney Docket No. ROO-039WO PATENTtypes of linkers can be used.

[0107] In some embodiments, the oligonucleotide molecule described herein is constructed using chemical synthesis and / or enzymatic ligation reactions using procedures known in the art. For example, the oligonucleotide molecule is chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the oligonucleotide molecule and target nucleic acids. Alternatively, the oligonucleotide molecule is produced biologically using an expression vector into which a oligonucleotide molecule has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted oligonucleotide molecule will be of an antisense orientation to a target polynucleic acid molecule of interest).

[0108] In some embodiments, the oligonucleotide molecule is synthesized via a tandem synthesis methodology, wherein both strands are synthesized as a single contiguous oligonucleotide fragment or strand separated by a cleavable linker which is subsequently cleaved to provide separate fragments or strands that hybridize and permit purification of the duplex.

[0109] As described herein, in some embodiments, the oligonucleotide molecule is a double stranded RNA molecule. In some embodiments, the oligonucleotide molecule can be modified to include a linker (L1) at the 5’-end of the of the sense strand (SS). In some embodiments, the oligonucleotide molecule can be modified to include a vinyl phosphonate or modified vinyl phosphonate at the 5’-end of the of the antisense strand (AS). In some embodiments, the oligonucleotide molecule can be modified to include a linker at the 3’-end of the sense strand (SS). In some embodiments, the oligonucleotide molecule can be modified to include a vinyl phosphonate at the 3’-end of the antisense strand (AS). The linker can be used to link the oligonucleotide molecule to an FN3 polypeptide. The linker can covalently attach, for example, to a cysteine residue on the FN3 polypeptide that is there naturally or that has been substituted. In some embodiments, the linker (L1) is covalently attached to an isolated FN3 polypeptide (F1) through a cysteine residue present on F1 that is there naturally 38 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT or that has been substituted. A cysteine substitution at a position in the FN3 polypeptide or protein comprises a replacement of the existing amino acid residue with a cysteine residue.

[0110] In some embodiments, F1 is conjugated to L1 through a cysteine on F1. In some embodiments, the cysteine is at a position as described herein. In some embodiments, the cysteine on F1 is 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 SEQ ID NO: 5. In some embodiments, the cysteine is located at a position that corresponds to residue 6, 54, or 88 of SEQ ID NO: 5.

[0111] In some embodiments, an FN3 polypeptide is conjugated to an siRNA molecule containing a cysteine residue using thiol-maleimide chemistry. In some embodiments, a cysteine‐containing FN3 polypeptide can be reduced in, for example, phosphate buffered saline or any other appropriate buffer with a reducing agent (e.g., tris(2‐ carboxyethyl) phosphine (TCEP)) to yield a free thiol. Then, in some embodiments, the free thiol-containing FN3 polypeptide was mixed with a maleimide linked‐modified siRNA duplex and incubated under conditions to form the linked complex. In some embodiments, the mixture is incubated for 0-5 hours, or about 1, 2, 3, 4, or 5 hours at room temperature. The reaction can be, for example, quenched with N‐ethyl maleimide. In some embodiments, the conjugates can be purified using affinity chromatography and ion-exchange chromatography. Other methods can also be used and this is simply one non-limiting embodiment.

[0112] In some embodiments, the oligonucleotide molecule provided for above comprises a linker (L1) at the 3’-end of the sense strand. In some embodiments, oligonucleotide molecule comprises a vinyl phosphonate at the 5’-end of the sense strand.

[0113] In some embodiments, the oligonucleotide molecule comprises an siRNA pair. In some embodiments, the siRNA pair is SEQ ID NO: 8 and SEQ ID NO: 9. In some embodiments, the siRNA pair is SEQ ID NO: 10 and SEQ ID NO: 11. In some embodiments, the siRNA pair is SEQ ID NO: 12 and SEQ ID NO: 13.

[0114] In some embodiments, the FN3 polypeptide that binds to the target protein is capable of being internalized into a cell. In some embodiments, internalization of the FN3 polypeptide may facilitate delivery of a detectable label or therapeutic into a cell. In some embodiments, internalization of the FN3 polypeptide may facilitate delivery of a cytotoxic agent into a cell. The cytotoxic agent can act as a therapeutic agent. In some embodiments, internalization of the FN3 polypeptide may facilitate the delivery of any detectable label, 39 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT therapeutic agent, and / or cytotoxic agent disclosed herein into a cell. In some embodiments, the cell is a tumor cell. In some embodiments, the cell is a liver cell, a lung cell, muscle cell, an immune cell, a dendritic cell, a cell of the CNS, or a heart cell. In some embodiments, the therapeutic agent is an siRNA molecule as provided for herein. The CD71-binding FN3 polypeptides conjugated to a detectable label can be used to evaluate expression of CD71 on samples such as tumor tissue in vivo or in vitro. The CD71-binding FN3 polypeptides conjugated to a detectable label can be used to evaluate expression of CD71 on samples such as blood, immune cells, muscle cells, or dendritic cells in vivo or in vitro. Pharmaceutical Compositions

[0115] As used herein, the terms “pharmaceutical composition” and “composition” may be used interchangeably.

[0116] Provided herein are compositions comprising macromolecules comprising an FN3 polypeptide linked to an oligonucleotide molecule.

[0117] In some embodiments, a composition is provided, wherein the pharmaceutical composition comprises an FN3 polypeptide, such as those provided herein, linked to an oligonucleotide, such as those provided herein.

[0118] In some embodiments, the pharmaceutical composition comprises an FN3 polypeptide linked to an oligonucleotide molecule, wherein the concentration of the FN3 polypeptide is about 1 mg / mL to about 100 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, or about 100 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 5 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 10 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 15 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 20 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 25 mg / mL. In some embodiments, the concentration of the FN3 polypeptide linked to the oligonucleotide is about 30 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 35 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 40 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 45 mg / mL. In some embodiments, the 40 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT concentration of the FN3 polypeptide is about 50 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 55 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 60 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 65 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 70 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 75 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 80 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 85 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 90 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 95 mg / mL. In some embodiments, the concentration of the FN3 polypeptide is about 100 mg / mL.

[0119] In some embodiments, the concentration of the FN3 polypeptide linked to the oligonucleotide is about 25 mg / mL, about 50 mg / mL, or about 75 mg / mL. In some embodiments, the concentration of the FN3 polypeptide linked to the oligonucleotide is about 50 mg / mL.

[0120] In some embodiments, the pharmaceutical composition is suitable for intravenous, subcutaneous, or intramuscular administration.

[0121] In some embodiments, a pharmaceutical dosage form is provided, wherein the pharmaceutical dosage form comprises the pharmaceutical composition as described herein. In some embodiments, the pharmaceutical dosage form is in a sterile, pyrogen free container. In some embodiments, the pharmaceutical dosage form is in a sterile, pyrogen free container, wherein the sterile, pyrogen free container is a syringe. In some embodiments, the pharmaceutical dosage form is in a sterile, pyrogen free container, wherein the sterile, pyrogen free container is a plastic vial. In some embodiments, the pharmaceutical dosage form is in a sterile, pyrogen free container, wherein the sterile, pyrogen free container is glass vial.

[0122] In some embodiments, a sterile, pyrogen free container is provided. In some embodiments, the sterile, pyrogen free container comprises the pharmaceutical composition as described herein. In some embodiments, the sterile, pyrogen free container comprises the pharmaceutical dosage form as described herein. In some embodiments, the sterile, pyrogen free container is a syringe. In some embodiments, the sterile, pyrogen free container is a plastic vial. In some embodiments, the sterile, pyrogen free container is glass vial. Dosing, Routes of Administration, and Methods of Use 41 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0123] As used herein, “subject” refers to any organism, such as an animal, including a mammal. A subject can be also be referred to as a patient. The term animal refers to any vertebrate or invertebrate animal. Vertebrate animals include mammals, birds, reptiles, fish, and amphibians. “Mammal” includes, but is not limited to, rodents (e.g., mice and rats), rabbits, dogs, cats, pigs, cattle, sheep, horses, non-human primates (e.g., monkeys), and humans. In some embodiments, the patient or subject is a human adult, adolescent, child or infant. In some embodiments, the patient or subject is an adolescent (i.e., 12-17 years old). In some embodiments, the patient or subject is younger than 2 years old. In some embodiments, the patient or subject is at least 18 years old. In some embodiments, the patient or subject is between the age of 18 and 75.

[0124] As used herein, a subject that is “in need thereof” refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition. The conditions can be, for example, any of the conditions described herein.

[0125] As used herein, “disease” refers to a disorder, condition, or illness, unless otherwise indicated.

[0126] As used herein, “inhibit” or “treat” refers to providing a treatment. “Treatment” refers to eliciting a clinically significant response without excessive levels of side effects; postponing or slowing of the development of the symptoms associated with a disease or disorder and / or a reduction in the severity of the symptoms of such disease or disorder; preventing additional symptoms, ameliorating or preventing the underlying causes of such symptoms, and improving or ameliorating existing uncontrolled or unwanted symptoms, or otherwise obtaining beneficial or desired clinical results. Thus, “inhibit,” “treat,” or “treatment” denote that a beneficial result has been conferred on, for example, a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, improvement or amelioration of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease; and prevention of disorder or disease manifestation. Treatment includes eliciting a clinically significant 42 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0127] As used herein, “prophylaxis,” “prophylactic measures,” and “preventative measures” refer to actions taken to prevent a disease or to delay the onset of a disease, especially by specified means or against a specified disease. The terms “prevent a disease,” “disease prevention,” and the like refer to prophylactic or preventative measures prior to overt disease or disorder onset to inhibit the full development or manifestation of a disease, or to minimize the extent of the disease, or to slow its course of development.

[0128] As used herein, “delay the onset of the disease,” “delay disease onset,” and the like refer to prophylactic or preventative measures prior to overt disease or disorder onset to slow its course of development or to delay disease onset compared to expected onset if not receiving prophylactic or preventative measures.

[0129] As used herein, “administer,” “administering,” or “administration” refer to either directly administering a compound or agent.

[0130] As used herein, “therapeutically effective amount,” “therapeutically effective dose,” and “effective amount” are interchangeable and refer to an amount of a therapeutic agent (such as an FN3 polypeptide-oligonucleotide conjugate) that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition. A therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. An effective amount of a therapeutic will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%. An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity. The actual amount which comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the 43 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0131] As used herein, “route of administration” refers to the location an agent is taken up into the body and the method by which the agent is administered to said location. Exemplary routes of administration include, but are not limited to, by mouth (oral), by injection, by inhalation, by insufflation (blowing into a body cavity), or by topical administration. Routes of administration may be combined, if desired. Oral administration includes the administration of any liquid, pill, capsule, or tablet that can be swallowed, chewed, or dissolved in the mouth. Alternatively, oral administration can refer to drinking or ingesting an agent that was added to a drink or food.

[0132] As used herein, “injection” refers to administering a fluid, such as a medicament, into a part of the body by using a needle. An injection can have a systemic or a local effect. An injection can be used for intraarterial, intraarticular, intracameral, intracerebral, intradermal, intramedullary, intramuscular, intraocular / intravitreal, intraperitoneal, intrathecal / intraspinal, intravenous, intraventricular, subcutaneous, suprachoroidal, or retroorbital administration, or for administration to any location within the body that can be punctured with a needle or a microneedle. An injection can also be an infusion, which refers to the continuous delivery of an agent through an intravenous or subcutaneous injection. In some embodiments, a therapeutic agent is administered. In some embodiments, an FN3 polypeptide-oligonucleotide conjugate composition is injected. In some embodiments, a pharmaceutical composition comprising an FN3 polypeptide- oligonucleotide conjugate composition is injected.

[0133] As used herein, “dose” and “dosage” refer to the physical form in which a drug is produced and dispensed, such as a tablet, a capsule, or an injectable. Doses can be administered one time, e.g., by a single bolus injection, by continuous infusion, or by doses can be administered on a schedule, e.g., every 4 hours, daily, 1-7 times per week, weekly, bi- weekly, monthly, bimonthly, quarterly, semiannually, annually, etc.

[0134] As used herein, “in combination with” and “co-administration” refer to two or more agents that can be administered to an animal or subject together in a mixture, concurrently or sequentially as single agents in any order. Unless otherwise described, the terms as used herein refer to the administration of a FN3 polypeptide-oligonucleotide conjugate and the administration of a second therapeutic agent. Therapeutic agents can be administered by the same or different route of administration or at the same or different time. 44 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0135] Toxicity and therapeutic efficacy of the FN3 polypeptide-oligonucleotide conjugate composition, administered alone or in combination with another agent, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index (LD50:ED50). In particular aspects, FN3 polypeptide-oligonucleotide conjugates exhibiting high therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the pharmaceutical dosage form employed and the route of administration.

[0136] Provided herein are pharmaceutical compositions comprising the FN3 polypeptide-oligonucleotide conjugate composition. In some embodiments, the pharmaceutical composition is administered to a subject. In some embodiments, the pharmaceutical composition comprising the FN3 polypeptide-oligonucleotide conjugate composition is administered to a subject in accordance with the Physicians’ Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)). Treatment of individuals may comprise the administration of a therapeutically effective amount of the FN3 polypeptide-oligonucleotide conjugate composition, as described herein.

[0137] In some embodiments, the pharmaceutical compositions can be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.

[0138] In some embodiments, the pharmaceutical compositions can be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent Nos.6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556, each of which is hereby incorporated by reference in its entirety.

[0139] In some embodiments, the pharmaceutical compositions can be administered by infusion. Examples of well-known implants and modules form administering pharmaceutical compositions include: U.S. Patent No.4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No.4,447,224, which discloses a variable flow implantable 45 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT infusion apparatus for continuous drug delivery; and U.S. Patent. No.4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0140] In some embodiments, the compositions provided herein can be administered via intravenous administration. In some embodiments, the compositions provided herein can be administered via subcutaneous administration. In some embodiments, the compositions provided herein can be administered via intramuscular administration.

[0141] Alternately, one may administer the FN3 polypeptide-oligonucleotide conjugate composition in a local rather than systemic manner, for example, via injection of the FN3 polypeptide-oligonucleotide conjugate composition directly into an arthritic joint or pathogen-induced lesion characterized by immunopathology, often in a depot or sustained release formulation. Furthermore, one may administer the FN3 polypeptide-oligonucleotide conjugate composition in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody.

[0142] The administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic FN3 polypeptide-oligonucleotide conjugate, the level of symptoms, the immunogenicity of the therapeutic FN3 polypeptide-oligonucleotide conjugate, and the accessibility of the target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic FN3 polypeptide-oligonucleotide conjugate, to effect improvement in the target disease state, while simultaneously minimizing undesired side effects. Accordingly, the amount of biologic delivered depends in part on the particular therapeutic FN3 polypeptide-oligonucleotide conjugate, and the severity of the condition being treated.

[0143] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate compositions as described herein are compatible with the recipient species such that an immune response to the FN3 polypeptide-oligonucleotide conjugate composition is not induced in the subject, or the immune response to the FN3 polypeptide-oligonucleotide conjugate composition does not result in an unacceptably short circulating half-life. In some embodiments, a pharmaceutical composition comprising the FN3 polypeptide- oligonucleotide conjugate composition is administered to a subject in accordance with the Physicians’ Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)). Treatment of individuals may comprise the administration of a therapeutically effective amount of the FN3 polypeptide-oligonucleotide conjugate composition, described herein. 46 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0144] Naturally, the amount of active ingredient in each therapeutically-useful composition may be prepared in such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half- life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable. Appropriate doses will depend on the subject being treated (e.g., human or nonhuman primate or other mammal), age and general condition of the subject to be treated, the severity of the condition being treated, the mode of administration, among other factors. An appropriate effective amount can be readily determined by one of skill in the art.

[0145] Determination of the appropriate dose can be made by the clinician, e.g., by using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures include, e.g., symptoms of inflammation or level of inflammatory cytokines produced. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized, and fully human FN3 domains may be desirable in the FN3 polypeptide-oligonucleotide conjugate composition.

[0146] Doses can be adjusted to optimize the effects in the subject. Additionally, a subject can be monitored for improvement of their condition prior to increasing the dosage.

[0147] In some embodiments, the composition comprises an FN3 polypeptide- oligonucleotide conjugate. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition comprises an FN3 polypeptide conjugated to an siRNA. In some embodiments, the composition is administered at a dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the composition is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 47 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0148] In some embodiments, the composition is administered at a dose of about 1 mg / kg. In some embodiments, the composition is administered at a dose of about 2 mg / kg. In some embodiments, the composition is administered at a dose of about 3 mg / kg. In some embodiments, the composition is administered at a dose of about 4 mg / kg. In some embodiments, the composition is administered at a dose of about 5 mg / kg. In some embodiments, the composition is administered at a dose of about 6 mg / kg. In some embodiments, the composition is administered at a dose of about 7 mg / kg. In some embodiments, the composition is administered at a dose of about 8 mg / kg. In some embodiments, the composition is administered at a dose of about 9 mg / kg. In some embodiments, the composition is administered at a dose of about 10 mg / kg. In some embodiments, the composition is administered at a dose of about 11 mg / kg. In some embodiments, the composition is administered at a dose of about 12 mg / kg. In some embodiments, the composition is administered at a dose of about 13 mg / kg. In some embodiments, the composition is administered at a dose of about 14 mg / kg. In some embodiments, the composition is administered at a dose of about 15 mg / kg. In some embodiments, the composition is administered at a dose of about 16 mg / kg. In some embodiments, the composition is administered at a dose of about 17 mg / kg. In some embodiments, the composition is administered at a dose of about 18 mg / kg. In some embodiments, the composition is administered at a dose of about 19 mg / kg. In some embodiments, the composition is administered at a dose of about 20 mg / kg. In some embodiments, the composition is administered at a dose of about 21 mg / kg. In some embodiments, the composition is administered at a dose of about 22 mg / kg. In some embodiments, the composition is administered at a dose of about 23 mg / kg. In some embodiments, the composition is administered at a dose of about 24 mg / kg. In some embodiments, the composition is administered at a dose of about 25 mg / kg. In some embodiments, the composition is administered at a dose of about 26 mg / kg. In some embodiments, the composition is administered at a dose of about 27 mg / kg. In some embodiments, the composition is administered at a dose of about 28 mg / kg. In some embodiments, the composition is administered at a dose of about 29 mg / kg. In some embodiments, the composition is administered at a dose of about 30 mg / kg. In some 48 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the composition is administered at a dose of about 31 mg / kg. In some embodiments, the composition is administered at a dose of about 32 mg / kg. In some embodiments, the composition is administered at a dose of about 33 mg / kg. In some embodiments, the composition is administered at a dose of about 34 mg / kg. In some embodiments, the composition is administered at a dose of about 35 mg / kg. In some embodiments, the composition is administered at a dose of about 36 mg / kg. In some embodiments, the composition is administered at a dose of about 37 mg / kg. In some embodiments, the composition is administered at a dose of about 38 mg / kg. In some embodiments, the composition is administered at a dose of about 39 mg / kg. In some embodiments, the composition is administered at a dose of about 40 mg / kg. In some embodiments, the composition is administered at a dose of about 41 mg / kg. In some embodiments, the composition is administered at a dose of about 42 mg / kg. In some embodiments, the composition is administered at a dose of about 43 mg / kg. In some embodiments, the composition is administered at a dose of about 44 mg / kg. In some embodiments, the composition is administered at a dose of about 45 mg / kg. In some embodiments, the composition is administered at a dose of about 46 mg / kg. In some embodiments, the composition is administered at a dose of about 47 mg / kg. In some embodiments, the composition is administered at a dose of about 48 mg / kg. In some embodiments, the composition is administered at a dose of about 49 mg / kg. In some embodiments, the composition is administered at a dose of about 50 mg / kg. In some embodiments, the composition is administered at a dose of about 51 mg / kg. In some embodiments, the composition is administered at a dose of about 52 mg / kg. In some embodiments, the composition is administered at a dose of about 53 mg / kg. In some embodiments, the composition is administered at a dose of about 54 mg / kg. In some embodiments, the composition is administered at a dose of about 55 mg / kg. In some embodiments, the composition is administered at a dose of about 56 mg / kg. In some embodiments, the composition is administered at a dose of about 57 mg / kg. In some embodiments, the composition is administered at a dose of about 58 mg / kg. In some embodiments, the composition is administered at a dose of about 59 mg / kg. In some embodiments, the composition is administered at a dose of about 60 mg / kg.

[0149] In some embodiments, the composition is administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 49 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0150] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0151] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 1 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 2 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 3 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 4 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 5 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 6 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 7 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 8 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 9 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 10 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 11 mg / kg. In some embodiments, 50 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 12 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 13 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 14 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 15 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 16 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 17 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 18 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 19 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 20 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 21 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 22 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 23 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 24 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 25 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 26 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 27 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 28 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 29 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 30 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 31 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 32 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 33 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 34 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 35 51 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 36 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 37 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 38 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 39 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 40 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 41 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 42 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 43 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 44 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 45 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 46 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 47 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 48 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 49 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 50 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 51 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 52 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 53 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 54 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 55 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 56 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 57 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a dose of about 58 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at 52 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT a dose of about 59 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a dose of about 60 mg / kg.

[0152] In some embodiments, the oligonucleotide is administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg.

[0153] In some embodiments, the oligonucleotide is administered at a dose of about 0.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 1.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 1.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 2.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 3.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 3.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 4.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 4.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 5.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 6.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 6.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 7.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 7.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 8.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 9.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 9.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 10.2 53 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 10.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 11.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 12.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 12.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 13.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 13.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 14.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 15.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 15.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 16.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 16.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 17.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 18.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 18.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 19.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 19.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 20.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 21.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 21.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 22.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 22.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 23.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 24.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 24.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 25.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 25.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 26.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 27.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 27.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 28.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 28.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 29.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 30.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 30.6 54 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 31.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 31.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 32.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 33.0 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 33.6 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 34.2 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 34.8 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 35.4 mg / kg. In some embodiments, the oligonucleotide is administered at a dose of about 36.0 mg / kg.

[0154] In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg to about 60 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the oligonucleotide at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 55 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0155] In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 0.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 2 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 1.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 3 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 1.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 4 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 2.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 5 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 3.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 6 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 3.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 7 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 4.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 8 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 4.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 9 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 5.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 10 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 6.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 11 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 6.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 12 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 7.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 13 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 7.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 14 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 8.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 15 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 9.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose 56 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT of about 16 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 9.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 17 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 10.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 18 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 10.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 19 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 11.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 20 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 12.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 21 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 12.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 22 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 13.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 23 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 13.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 24 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 14.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 25 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 15.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 26 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 15.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 27 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 16.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 28 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 16.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 29 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 17.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 30 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 18.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 31 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 18.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 32 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 19.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose 57 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT of about 33 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 19.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 34 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 20.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 35 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 21.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 36 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 21.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 37 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 22.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 38 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 22.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 39 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 23.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 40 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 24.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 41 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 24.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 42 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 25.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 43 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 25.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 44 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 26.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 45 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 27.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 46 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 27.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 47 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 28.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 48 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 28.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 49 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 29.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose 58 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT of about 50 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 30.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 51 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 30.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 52 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 31.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 53 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 31.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 54 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 32.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 55 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 33.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 56 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 33.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 57 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 34.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 58 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 34.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 59 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 35.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 60 mg / kg wherein the oligonucleotide of the conjugate composition is at a dose of about 36.0 mg / kg.

[0156] In some embodiments, the composition administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg, comprises the oligonucleotide at a dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 59 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, or 36.0 mg / kg, respectively.

[0157] In some embodiments, the siRNA is administered at a dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg.

[0158] In some embodiments, the siRNA is administered at a dose of about 0.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 1.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 1.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 2.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 3.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 3.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 4.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 4.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 5.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 6.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 6.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 7.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 7.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 8.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 9.0 mg / kg. In some 60 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the siRNA is administered at a dose of about 9.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 10.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 10.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 11.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 12.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 12.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 13.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 13.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 14.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 15.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 15.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 16.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 16.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 17.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 18.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 18.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 19.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 19.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 20.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 21.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 21.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 22.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 22.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 23.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 24.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 24.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 25.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 25.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 26.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 27.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 27.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 28.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 28.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 29.4 mg / kg. In some 61 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the siRNA is administered at a dose of about 30.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 30.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 31.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 31.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 32.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 33.0 mg / kg. In some embodiments, the siRNA is administered at a dose of about 33.6 mg / kg. In some embodiments, the siRNA is administered at a dose of about 34.2 mg / kg. In some embodiments, the siRNA is administered at a dose of about 34.8 mg / kg. In some embodiments, the siRNA is administered at a dose of about 35.4 mg / kg. In some embodiments, the siRNA is administered at a dose of about 36.0 mg / kg.

[0159] In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg to about 60 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the siRNA at a dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 62 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0160] In some embodiments, the conjugate composition is administered at a dose of about 1 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 0.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 2 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 1.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 3 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 1.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 4 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 2.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 5 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 3.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 6 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 3.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 7 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 4.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 8 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 4.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 9 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 5.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 10 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 6.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 11 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 6.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 12 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 7.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 13 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 7.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 14 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 8.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 15 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 9.0 mg / kg. In some 63 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the conjugate composition is administered at a dose of about 16 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 9.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 17 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 10.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 18 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 10.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 19 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 11.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 20 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 12.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 21 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 12.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 22 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 13.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 23 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 13.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 24 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 14.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 25 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 15.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 26 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 15.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 27 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 16.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 28 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 16.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 29 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 17.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 30 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 18.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 31 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 18.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 32 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 19.2 mg / kg. In some 64 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the conjugate composition is administered at a dose of about 33 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 19.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 34 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 20.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 35 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 21.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 36 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 21.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 37 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 22.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 38 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 22.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 39 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 23.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 40 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 24.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 41 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 24.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 42 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 25.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 43 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 25.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 44 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 26.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 45 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 27.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 46 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 27.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 47 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 28.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 48 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 28.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 49 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 29.4 mg / kg. In some 65 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the conjugate composition is administered at a dose of about 50 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 30.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 51 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 30.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 52 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 31.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 53 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 31.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 54 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 32.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 55 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 33.0 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 56 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 33.6 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 57 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 34.2 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 58 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 34.8 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 59 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 35.4 mg / kg. In some embodiments, the conjugate composition is administered at a dose of about 60 mg / kg wherein the siRNA of the conjugate composition is at a dose of about 36.0 mg / kg.

[0161] In some embodiments, the composition administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg, comprises the siRNA at a dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 66 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, or 36.0 mg / kg, respectively.

[0162] In some embodiments, the composition is administered at a first dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the composition is administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0163] In some embodiments, the composition is administered at a first dose of about 1 mg / kg. In some embodiments, the composition is administered at a first dose of about 2 mg / kg. In some embodiments, the composition is administered at a first dose of about 3 mg / kg. In some embodiments, the composition is administered at a first dose of about 4 mg / kg. In some embodiments, the composition is administered at a first dose of about 5 mg / kg. In some embodiments, the composition is administered at a first dose of about 6 mg / kg. In some embodiments, the composition is administered at a first dose of about 7 mg / kg. In some embodiments, the composition is administered at a first dose of about 8 mg / kg. In some embodiments, the composition is administered at a first dose of about 9 mg / kg. In some embodiments, the composition is administered at a first dose of about 10 mg / kg. In some embodiments, the composition is administered at a first dose of about 11 mg / kg. In some embodiments, the composition is administered at a first dose of about 12 mg / kg. In some embodiments, the composition is administered at a first dose of about 13 mg / kg. In some embodiments, the composition is administered at a first dose of about 14 mg / kg. In some embodiments, the composition is administered at a first dose of about 15 mg / kg. In some embodiments, the composition is administered at a first dose of about 16 67 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg. In some embodiments, the composition is administered at a first dose of about 17 mg / kg. In some embodiments, the composition is administered at a first dose of about 18 mg / kg. In some embodiments, the composition is administered at a first dose of about 19 mg / kg. In some embodiments, the composition is administered at a first dose of about 20 mg / kg. In some embodiments, the composition is administered at a first dose of about 21 mg / kg. In some embodiments, the composition is administered at a first dose of about 22 mg / kg. In some embodiments, the composition is administered at a first dose of about 23 mg / kg. In some embodiments, the composition is administered at a first dose of about 24 mg / kg. In some embodiments, the composition is administered at a first dose of about 25 mg / kg. In some embodiments, the composition is administered at a first dose of about 26 mg / kg. In some embodiments, the composition is administered at a first dose of about 27 mg / kg. In some embodiments, the composition is administered at a first dose of about 28 mg / kg. In some embodiments, the composition is administered at a first dose of about 29 mg / kg. In some embodiments, the composition is administered at a first dose of about 30 mg / kg. In some embodiments, the composition is administered at a first dose of about 31 mg / kg. In some embodiments, the composition is administered at a first dose of about 32 mg / kg. In some embodiments, the composition is administered at a first dose of about 33 mg / kg. In some embodiments, the composition is administered at a first dose of about 34 mg / kg. In some embodiments, the composition is administered at a first dose of about 35 mg / kg. In some embodiments, the composition is administered at a first dose of about 36 mg / kg. In some embodiments, the composition is administered at a first dose of about 37 mg / kg. In some embodiments, the composition is administered at a first dose of about 38 mg / kg. In some embodiments, the composition is administered at a first dose of about 39 mg / kg. In some embodiments, the composition is administered at a first dose of about 40 mg / kg. In some embodiments, the composition is administered at a first dose of about 41 mg / kg. In some embodiments, the composition is administered at a first dose of about 42 mg / kg. In some embodiments, the composition is administered at a first dose of about 43 mg / kg. In some embodiments, the composition is administered at a first dose of about 44 mg / kg. In some embodiments, the composition is administered at a first dose of about 45 mg / kg. In some embodiments, the composition is administered at a first dose of about 46 mg / kg. In some embodiments, the composition is administered at a first dose of about 47 mg / kg. In some embodiments, the composition is administered at a first dose of about 48 mg / kg. In some embodiments, the composition is administered at a first dose of about 49 mg / kg. In some embodiments, the composition is administered at a first dose of about 50 68 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg. In some embodiments, the composition is administered at a first dose of about 51 mg / kg. In some embodiments, the composition is administered at a first dose of about 52 mg / kg. In some embodiments, the composition is administered at a first dose of about 53 mg / kg. In some embodiments, the composition is administered at a first dose of about 54 mg / kg. In some embodiments, the composition is administered at a first dose of about 55 mg / kg. In some embodiments, the composition is administered at a first dose of about 56 mg / kg. In some embodiments, the composition is administered at a first dose of about 57 mg / kg. In some embodiments, the composition is administered at a first dose of about 58 mg / kg. In some embodiments, the composition is administered at a first dose of about 59 mg / kg. In some embodiments, the composition is administered at a first dose of about 60 mg / kg.

[0164] In some embodiments, the composition is administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0165] In some embodiments, the composition is administered at a one or more subsequent dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg. 69 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT

[0166] In some embodiments, the composition is administered at a one or more subsequent dose of about 1 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 2 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 3 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 4 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 5 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 6 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 7 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 8 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 9 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 10 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 11 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 12 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 13 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 14 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 15 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 16 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 17 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 18 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 19 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 20 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 21 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 22 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 23 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 24 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 25 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 26 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 27 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 28 mg / kg. In some embodiments, the 70 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT composition is administered at a one or more subsequent dose of about 29 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 30 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 31 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 32 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 33 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 34 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 35 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 36 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 37 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 38 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 39 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 40 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 41 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 42 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 43 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 44 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 45 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 46 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 47 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 48 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 49 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 50 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 51 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 52 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 53 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 54 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 55 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 56 mg / kg. In some embodiments, the composition is administered at a one or 71 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT more subsequent dose of about 57 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 58 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 59 mg / kg. In some embodiments, the composition is administered at a one or more subsequent dose of about 60 mg / kg.

[0167] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0168] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 1 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 2 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 3 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 4 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 5 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 6 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 7 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 8 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 9 mg / kg. In some embodiments, the FN3 polypeptide- 72 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT oligonucleotide conjugate composition is administered at a first dose of about 10 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 11 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 12 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 13 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 14 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 15 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 16 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 17 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 18 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 19 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 20 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 21 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 22 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 23 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 24 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 25 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 26 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 27 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 28 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 29 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 30 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 31 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 32 mg / kg. In 73 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 33 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 34 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 35 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 36 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 37 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 38 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 39 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 40 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 41 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 42 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 43 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 44 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 45 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 46 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 47 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 48 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 49 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 50 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 51 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 52 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 53 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 54 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is 74 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT administered at a first dose of about 55 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 56 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 57 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 58 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of about 59 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a first dose of about 60 mg / kg.

[0169] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0170] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0171] In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 1 mg / kg. In some 75 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 2 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 3 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 4 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 5 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 6 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 7 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 8 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 9 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 10 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 11 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 12 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 13 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 14 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 15 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 16 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 17 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 18 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 19 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 20 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate 76 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT composition is administered at a one or more subsequent dose of about 21 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 22 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 23 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 24 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 25 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 26 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 27 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 28 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 29 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 30 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 31 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 32 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 33 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 34 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 35 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 36 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 37 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 38 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 39 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of 77 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 40 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 41 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 42 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 43 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 44 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 45 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 46 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 47 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 48 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 49 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 50 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 51 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 52 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 53 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 54 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 55 mg / kg. In some embodiments, the FN3 polypeptide- oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 56 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 57 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 58 mg / kg. In some embodiments, the FN3 polypeptide-oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 59 mg / kg. In some embodiments, the FN3 polypeptide- 78 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT oligonucleotide conjugate composition is administered at a one or more subsequent dose of about 60 mg / kg.

[0172] In some embodiments, the oligonucleotide is administered at a first dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg..

[0173] In some embodiments, the oligonucleotide is administered at a first dose of about 0.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 1.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 1.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 2.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 3.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 3.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 4.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 4.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 5.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 6.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 6.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 7.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 7.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 8.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 9.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 9.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of 79 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 10.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 10.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 11.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 12.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 12.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 13.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 13.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 14.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 15.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 15.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 16.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 16.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 17.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 18.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 18.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 19.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 19.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 20.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 21.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 21.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 22.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 22.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 23.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 24.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 24.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 25.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 25.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 26.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 27.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 27.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 28.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 28.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 29.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 30.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of 80 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 30.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 31.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 31.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 32.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 33.0 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 33.6 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 34.2 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 34.8 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 35.4 mg / kg. In some embodiments, the oligonucleotide is administered at a first dose of about 36.0 mg / kg.

[0174] In some embodiments, the oligonucleotide is administered at a first dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, 36.0 mg / kg.

[0175] In some embodiments, the composition administered at a first dose of about 1 mg / kg to about 60 mg / kg comprises the oligonucleotide at a first dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the composition administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the 81 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT oligonucleotide at a first dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0176] In some embodiments, the composition administered at a first dose of about 1 mg / kg comprises the oligonucleotide at a first dose of about 0.6 mg / kg. In some embodiments, the composition administered at a first dose of about 2 mg / kg comprises the oligonucleotide at a first dose of about 1.2 mg / kg. In some embodiments, the composition administered at a first dose of about 3 mg / kg comprises the oligonucleotide at a first dose of about 1.8 mg / kg. In some embodiments, the composition administered at a first dose of about 4 mg / kg comprises the oligonucleotide at a first dose of about 2.4 mg / kg. In some embodiments, the composition administered at a first dose of about 5 mg / kg comprises the oligonucleotide at a first dose of about 3.0 mg / kg. In some embodiments, the composition administered at a first dose of about 6 mg / kg comprises the oligonucleotide at a first dose of about 3.6 mg / kg. In some embodiments, the composition administered at a first dose of about 7 mg / kg comprises the oligonucleotide at a first dose of about 4.2 mg / kg. In some embodiments, the composition administered at a first dose of about 8 mg / kg comprises the oligonucleotide at a first dose of about 4.8 mg / kg. In some embodiments, the composition administered at a first dose of about 9 mg / kg comprises the oligonucleotide at a first dose of about 5.4 mg / kg. In some embodiments, the composition administered at a first dose of about 10 mg / kg comprises the oligonucleotide at a first dose of about 6.0 mg / kg. In some embodiments, the composition administered at a first dose of about 11 mg / kg comprises the oligonucleotide at a first dose of about 6.6 mg / kg. In some embodiments, the composition administered at a first dose of about 12 mg / kg comprises the oligonucleotide at a first dose of about 7.2 mg / kg. In some embodiments, the composition administered at a first dose of about 82 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 13 mg / kg comprises the oligonucleotide at a first dose of about 7.8 mg / kg. In some embodiments, the composition administered at a first dose of about 14 mg / kg comprises the oligonucleotide at a first dose of about 8.4 mg / kg. In some embodiments, the composition administered at a first dose of about 15 mg / kg comprises the oligonucleotide at a first dose of about 9.0 mg / kg. In some embodiments, the composition administered at a first dose of about 16 mg / kg comprises the oligonucleotide at a first dose of about 9.6 mg / kg. In some embodiments, the composition administered at a first dose of about 17 mg / kg comprises the oligonucleotide at a first dose of about 10.2 mg / kg. In some embodiments, the composition administered at a first dose of about 18 mg / kg comprises the oligonucleotide at a first dose of about 10.8 mg / kg. In some embodiments, the composition administered at a first dose of about 19 mg / kg comprises the oligonucleotide at a first dose of about 11.4 mg / kg. In some embodiments, the composition administered at a first dose of about 20 mg / kg comprises the oligonucleotide at a first dose of about 12.0 mg / kg. In some embodiments, the composition administered at a first dose of about 21 mg / kg comprises the oligonucleotide at a first dose of about 12.6 mg / kg. In some embodiments, the composition administered at a first dose of about 22 mg / kg comprises the oligonucleotide at a first dose of about 13.2 mg / kg. In some embodiments, the composition administered at a first dose of about 23 mg / kg comprises the oligonucleotide at a first dose of about 13.8 mg / kg. In some embodiments, the composition administered at a first dose of about 24 mg / kg comprises the oligonucleotide at a first dose of about 14.4 mg / kg. In some embodiments, the composition administered at a first dose of about 25 mg / kg comprises the oligonucleotide at a first dose of about 15.0 mg / kg. In some embodiments, the composition administered at a first dose of about 26 mg / kg comprises the oligonucleotide at a first dose of about 15.6 mg / kg. In some embodiments, the composition administered at a first dose of about 27 mg / kg comprises the oligonucleotide at a first dose of about 16.2 mg / kg. In some embodiments, the composition administered at a first dose of about 28 mg / kg comprises the oligonucleotide at a first dose of about 16.8 mg / kg. In some embodiments, the composition administered at a first dose of about 29 mg / kg comprises the oligonucleotide at a first dose of about 17.4 mg / kg. In some embodiments, the composition administered at a first dose of about 30 mg / kg comprises the oligonucleotide at a first dose of about 18.0 mg / kg. In some embodiments, the composition administered at a first dose of about 31 mg / kg comprises the oligonucleotide at a first dose of about 18.6 mg / kg. In some embodiments, the composition administered at a first dose of about 32 mg / kg comprises the oligonucleotide at a first dose of about 19.2 mg / kg. In some embodiments, the composition administered at a first dose of about 33 mg / kg comprises the oligonucleotide at a first dose of 83 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 19.8 mg / kg. In some embodiments, the composition administered at a first dose of about 34 mg / kg comprises the oligonucleotide at a first dose of about 20.4 mg / kg. In some embodiments, the composition administered at a first dose of about 35 mg / kg comprises the oligonucleotide at a first dose of about 21.0 mg / kg. In some embodiments, the composition administered at a first dose of about 36 mg / kg comprises the oligonucleotide at a first dose of about 21.6 mg / kg. In some embodiments, the composition administered at a first dose of about 37 mg / kg comprises the oligonucleotide at a first dose of about 22.2 mg / kg. In some embodiments, the composition administered at a first dose of about 38 mg / kg comprises the oligonucleotide at a first dose of about 22.8 mg / kg. In some embodiments, the composition administered at a first dose of about 39 mg / kg comprises the oligonucleotide at a first dose of about 23.4 mg / kg. In some embodiments, the composition administered at a first dose of about 40 mg / kg comprises the oligonucleotide at a first dose of about 24.0 mg / kg. In some embodiments, the composition administered at a first dose of about 41 mg / kg comprises the oligonucleotide at a first dose of about 24.6 mg / kg. In some embodiments, the composition administered at a first dose of about 42 mg / kg comprises the oligonucleotide at a first dose of about 25.2 mg / kg. In some embodiments, the composition administered at a first dose of about 43 mg / kg comprises the oligonucleotide at a first dose of about 25.8 mg / kg. In some embodiments, the composition administered at a first dose of about 44 mg / kg comprises the oligonucleotide at a first dose of about 26.4 mg / kg. In some embodiments, the composition administered at a first dose of about 45 mg / kg comprises the oligonucleotide at a first dose of about 27.0 mg / kg. In some embodiments, the composition administered at a first dose of about 46 mg / kg comprises the oligonucleotide at a first dose of about 27.6 mg / kg. In some embodiments, the composition administered at a first dose of about 47 mg / kg comprises the oligonucleotide at a first dose of about 28.2 mg / kg. In some embodiments, the composition administered at a first dose of about 48 mg / kg comprises the oligonucleotide at a first dose of about 28.8 mg / kg. In some embodiments, the composition administered at a first dose of about 49 mg / kg comprises the oligonucleotide at a first dose of about 29.4 mg / kg. In some embodiments, the composition administered at a first dose of about 50 mg / kg comprises the oligonucleotide at a first dose of about 30.0 mg / kg. In some embodiments, the composition administered at a first dose of about 51 mg / kg comprises the oligonucleotide at a first dose of about 30.6 mg / kg. In some embodiments, the composition administered at a first dose of about 52 mg / kg comprises the oligonucleotide at a first dose of about 31.2 mg / kg. In some embodiments, the composition administered at a first dose of about 53 mg / kg comprises the oligonucleotide at a first dose of about 31.8 mg / kg. In some embodiments, the composition 84 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT administered at a first dose of about 54 mg / kg comprises the oligonucleotide at a first dose of about 32.4 mg / kg. In some embodiments, the composition administered at a first dose of about 55 mg / kg comprises the oligonucleotide at a first dose of about 33.0 mg / kg. In some embodiments, the composition administered at a first dose of about 56 mg / kg comprises the oligonucleotide at a first dose of about 33.6 mg / kg. In some embodiments, the composition administered at a first dose of about 57 mg / kg comprises the oligonucleotide at a first dose of about 34.2 mg / kg. In some embodiments, the composition administered at a first dose of about 58 mg / kg comprises the oligonucleotide at a first dose of about 34.8 mg / kg. In some embodiments, the composition administered at a first dose of about 59 mg / kg comprises the oligonucleotide at a first dose of about 35.4 mg / kg. In some embodiments, the composition administered at a first dose of about 60 mg / kg comprises the oligonucleotide at a first dose of about 36.0 mg / kg.

[0177] In some embodiments, the composition administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg, comprises the oligonucleotide at a first dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, or 36.0 mg / kg, respectively.

[0178] In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the oligonucleotide is administered at one or more subsequent dose of about 0.6 mg / kg, about 1.2 85 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg.

[0179] In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 0.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 1.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 1.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 2.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 3.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 3.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 4.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 4.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 5.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 6.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 6.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 7.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 7.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 8.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 9.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 9.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 10.2 mg / kg. In some embodiments, the oligonucleotide is 86 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT administered at a one or more subsequent dose of about 10.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 11.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 12.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 12.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 13.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 13.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 14.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 15.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 15.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 16.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 16.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 17.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 18.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 18.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 19.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 19.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 20.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 21.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 21.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 22.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 22.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 23.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 24.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 24.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 25.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 25.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 26.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or 87 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT more subsequent dose of about 27.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 27.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 28.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 28.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 29.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 30.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 30.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 31.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 31.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 32.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 33.0 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 33.6 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 34.2 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 34.8 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 35.4 mg / kg. In some embodiments, the oligonucleotide is administered at a one or more subsequent dose of about 36.0 mg / kg.

[0180] In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg to about 60 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 88 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the oligonucleotide at a one or more subsequent dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0181] In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 0.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 2 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 1.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 3 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 1.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 4 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 2.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 5 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 3.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 6 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 3.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 7 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 4.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 8 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 4.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 9 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 5.4 mg / kg. In some embodiments, the composition administered at a one or more 89 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT subsequent dose of about 10 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 6.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 11 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 6.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 12 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 7.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 13 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 7.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 14 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 8.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 15 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 9.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 16 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 9.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 17 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 10.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 18 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 10.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 19 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 11.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 20 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 12.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 21 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 12.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 22 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 13.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 23 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 13.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 24 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 14.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 25 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 15.0 mg / kg. In some 90 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the composition administered at a one or more subsequent dose of about 26 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 15.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 27 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 16.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 28 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 16.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 29 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 17.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 30 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 18.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 31 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 18.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 32 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 19.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 33 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 19.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 34 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 20.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 35 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 21.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 36 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 21.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 37 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 22.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 38 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 22.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 39 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 23.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 40 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 24.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 41 mg / kg comprises the oligonucleotide at a one or more 91 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT subsequent dose of about 24.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 42 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 25.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 43 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 25.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 44 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 26.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 45 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 27.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 46 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 27.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 47 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 28.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 48 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 28.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 49 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 29.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 50 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 30.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 51 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 30.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 52 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 31.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 53 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 31.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 54 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 32.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 55 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 33.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 56 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 33.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of 92 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 57 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 34.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 58 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 34.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 59 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 35.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 60 mg / kg comprises the oligonucleotide at a one or more subsequent dose of about 36.0 mg / kg.

[0182] In some embodiments, the composition administered at a one or more subsequent dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg, comprises the oligonucleotide at a one or more subsequent dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, or 36.0 mg / kg, respectively.

[0183] In some embodiments, the siRNA is administered at a first dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 93 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg..

[0184] In some embodiments, the siRNA is administered at a first dose of about 0.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 1.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 1.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 2.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 3.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 3.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 4.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 4.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 5.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 6.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 6.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 7.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 7.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 8.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 9.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 9.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 10.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 10.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 11.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 12.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 12.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 13.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 13.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 14.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 15.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 15.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 16.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 16.8 mg / kg. In some 94 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT embodiments, the siRNA is administered at a first dose of about 17.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 18.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 18.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 19.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 19.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 20.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 21.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 21.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 22.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 22.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 23.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 24.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 24.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 25.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 25.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 26.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 27.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 27.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 28.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 28.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 29.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 30.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 30.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 31.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 31.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 32.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 33.0 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 33.6 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 34.2 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 34.8 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 35.4 mg / kg. In some embodiments, the siRNA is administered at a first dose of about 36.0 mg / kg.

[0185] In some embodiments, the siRNA is administered at a first dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 95 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, 36.0 mg / kg.

[0186] In some embodiments, the composition administered at a first dose of about 1 mg / kg to about 60 mg / kg comprises the siRNA at a first dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the composition administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the siRNA at a first dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 96 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0187] In some embodiments, the composition administered at a first dose of about 1 mg / kg comprises the siRNA at a first dose of about 0.6 mg / kg. In some embodiments, the composition administered at a first dose of about 2 mg / kg comprises the siRNA at a first dose of about 1.2 mg / kg. In some embodiments, the composition administered at a first dose of about 3 mg / kg comprises the siRNA at a first dose of about 1.8 mg / kg. In some embodiments, the composition administered at a first dose of about 4 mg / kg comprises the siRNA at a first dose of about 2.4 mg / kg. In some embodiments, the composition administered at a first dose of about 5 mg / kg comprises the siRNA at a first dose of about 3.0 mg / kg. In some embodiments, the composition administered at a first dose of about 6 mg / kg comprises the siRNA at a first dose of about 3.6 mg / kg. In some embodiments, the composition administered at a first dose of about 7 mg / kg comprises the siRNA at a first dose of about 4.2 mg / kg. In some embodiments, the composition administered at a first dose of about 8 mg / kg comprises the siRNA at a first dose of about 4.8 mg / kg. In some embodiments, the composition administered at a first dose of about 9 mg / kg comprises the siRNA at a first dose of about 5.4 mg / kg. In some embodiments, the composition administered at a first dose of about 10 mg / kg comprises the siRNA at a first dose of about 6.0 mg / kg. In some embodiments, the composition administered at a first dose of about 11 mg / kg comprises the siRNA at a first dose of about 6.6 mg / kg. In some embodiments, the composition administered at a first dose of about 12 mg / kg comprises the siRNA at a first dose of about 7.2 mg / kg. In some embodiments, the composition administered at a first dose of about 13 mg / kg comprises the siRNA at a first dose of about 7.8 mg / kg. In some embodiments, the composition administered at a first dose of about 14 mg / kg comprises the siRNA at a first dose of about 8.4 mg / kg. In some embodiments, the composition administered at a first dose of about 15 mg / kg comprises the siRNA at a first dose of about 9.0 mg / kg. In some embodiments, the composition administered at a first dose of about 16 mg / kg comprises the siRNA at a first dose of about 9.6 mg / kg. In some embodiments, the composition administered at a first dose of about 17 mg / kg comprises the siRNA at a first dose of about 10.2 mg / kg. In some embodiments, the composition administered at a first dose of about 18 mg / kg comprises the siRNA at a first dose of about 10.8 mg / kg. In some embodiments, the composition administered at a first dose of about 19 mg / kg comprises the siRNA at a first dose of about 11.4 mg / kg. In some embodiments, the composition administered at a first dose of about 20 mg / kg comprises the siRNA at a first dose of about 97 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 12.0 mg / kg. In some embodiments, the composition administered at a first dose of about 21 mg / kg comprises the siRNA at a first dose of about 12.6 mg / kg. In some embodiments, the composition administered at a first dose of about 22 mg / kg comprises the siRNA at a first dose of about 13.2 mg / kg. In some embodiments, the composition administered at a first dose of about 23 mg / kg comprises the siRNA at a first dose of about 13.8 mg / kg. In some embodiments, the composition administered at a first dose of about 24 mg / kg comprises the siRNA at a first dose of about 14.4 mg / kg. In some embodiments, the composition administered at a first dose of about 25 mg / kg comprises the siRNA at a first dose of about 15.0 mg / kg. In some embodiments, the composition administered at a first dose of about 26 mg / kg comprises the siRNA at a first dose of about 15.6 mg / kg. In some embodiments, the composition administered at a first dose of about 27 mg / kg comprises the siRNA at a first dose of about 16.2 mg / kg. In some embodiments, the composition administered at a first dose of about 28 mg / kg comprises the siRNA at a first dose of about 16.8 mg / kg. In some embodiments, the composition administered at a first dose of about 29 mg / kg comprises the siRNA at a first dose of about 17.4 mg / kg. In some embodiments, the composition administered at a first dose of about 30 mg / kg comprises the siRNA at a first dose of about 18.0 mg / kg. In some embodiments, the composition administered at a first dose of about 31 mg / kg comprises the siRNA at a first dose of about 18.6 mg / kg. In some embodiments, the composition administered at a first dose of about 32 mg / kg comprises the siRNA at a first dose of about 19.2 mg / kg. In some embodiments, the composition administered at a first dose of about 33 mg / kg comprises the siRNA at a first dose of about 19.8 mg / kg. In some embodiments, the composition administered at a first dose of about 34 mg / kg comprises the siRNA at a first dose of about 20.4 mg / kg. In some embodiments, the composition administered at a first dose of about 35 mg / kg comprises the siRNA at a first dose of about 21.0 mg / kg. In some embodiments, the composition administered at a first dose of about 36 mg / kg comprises the siRNA at a first dose of about 21.6 mg / kg. In some embodiments, the composition administered at a first dose of about 37 mg / kg comprises the siRNA at a first dose of about 22.2 mg / kg. In some embodiments, the composition administered at a first dose of about 38 mg / kg comprises the siRNA at a first dose of about 22.8 mg / kg. In some embodiments, the composition administered at a first dose of about 39 mg / kg comprises the siRNA at a first dose of about 23.4 mg / kg. In some embodiments, the composition administered at a first dose of about 40 mg / kg comprises the siRNA at a first dose of about 24.0 mg / kg. In some embodiments, the composition administered at a first dose of about 41 mg / kg comprises the siRNA at a first dose of about 24.6 mg / kg. In some embodiments, the 98 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT composition administered at a first dose of about 42 mg / kg comprises the siRNA at a first dose of about 25.2 mg / kg. In some embodiments, the composition administered at a first dose of about 43 mg / kg comprises the siRNA at a first dose of about 25.8 mg / kg. In some embodiments, the composition administered at a first dose of about 44 mg / kg comprises the siRNA at a first dose of about 26.4 mg / kg. In some embodiments, the composition administered at a first dose of about 45 mg / kg comprises the siRNA at a first dose of about 27.0 mg / kg. In some embodiments, the composition administered at a first dose of about 46 mg / kg comprises the siRNA at a first dose of about 27.6 mg / kg. In some embodiments, the composition administered at a first dose of about 47 mg / kg comprises the siRNA at a first dose of about 28.2 mg / kg. In some embodiments, the composition administered at a first dose of about 48 mg / kg comprises the siRNA at a first dose of about 28.8 mg / kg. In some embodiments, the composition administered at a first dose of about 49 mg / kg comprises the siRNA at a first dose of about 29.4 mg / kg. In some embodiments, the composition administered at a first dose of about 50 mg / kg comprises the siRNA at a first dose of about 30.0 mg / kg. In some embodiments, the composition administered at a first dose of about 51 mg / kg comprises the siRNA at a first dose of about 30.6 mg / kg. In some embodiments, the composition administered at a first dose of about 52 mg / kg comprises the siRNA at a first dose of about 31.2 mg / kg. In some embodiments, the composition administered at a first dose of about 53 mg / kg comprises the siRNA at a first dose of about 31.8 mg / kg. In some embodiments, the composition administered at a first dose of about 54 mg / kg comprises the siRNA at a first dose of about 32.4 mg / kg. In some embodiments, the composition administered at a first dose of about 55 mg / kg comprises the siRNA at a first dose of about 33.0 mg / kg. In some embodiments, the composition administered at a first dose of about 56 mg / kg comprises the siRNA at a first dose of about 33.6 mg / kg. In some embodiments, the composition administered at a first dose of about 57 mg / kg comprises the siRNA at a first dose of about 34.2 mg / kg. In some embodiments, the composition administered at a first dose of about 58 mg / kg comprises the siRNA at a first dose of about 34.8 mg / kg. In some embodiments, the composition administered at a first dose of about 59 mg / kg comprises the siRNA at a first dose of about 35.4 mg / kg. In some embodiments, the composition administered at a first dose of about 60 mg / kg comprises the siRNA at a first dose of about 36.0 mg / kg.

[0188] In some embodiments, the composition administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 99 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg, comprises the siRNA at a first dose of 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.6 mg / kg, 4.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 6.0 mg / kg, 6.6 mg / kg, 7.2 mg / kg, 7.8 mg / kg, 8.4 mg / kg, 9.0 mg / kg, 9.6 mg / kg, 10.2 mg / kg, 10.8 mg / kg, 11.4 mg / kg, 12.0 mg / kg, 12.6 mg / kg, 13.2 mg / kg, 13.8 mg / kg, 14.4 mg / kg, 15.0 mg / kg, 15.6 mg / kg, 16.2 mg / kg, 16.8 mg / kg, 17.4 mg / kg, 18.0 mg / kg, 18.6 mg / kg, 19.2 mg / kg, 19.8 mg / kg, 20.4 mg / kg, 21.0 mg / kg, 21.6 mg / kg, 22.2 mg / kg, 22.8 mg / kg, 23.4 mg / kg, 24.0 mg / kg, 24.6 mg / kg, 25.2 mg / kg, 25.8 mg / kg, 26.4 mg / kg, 27.0 mg / kg, 27.6 mg / kg, 28.2 mg / kg, 28.8 mg / kg, 29.4 mg / kg, 30.0 mg / kg, 30.6 mg / kg, 31.2 mg / kg, 31.8 mg / kg, 32.4 mg / kg, 33.0 mg / kg, 33.6 mg / kg, 34.2 mg / kg, 34.8 mg / kg, 35.4 mg / kg, or 36.0 mg / kg, respectively.

[0189] In some embodiments, the siRNA is administered at a one or more subsequent dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the siRNA is administered at one or more subsequent dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg.

[0190] In some embodiments, the siRNA is administered at a one or more subsequent dose of about 0.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 1.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 1.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 2.4 mg / kg. In some embodiments, the 100 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT siRNA is administered at a one or more subsequent dose of about 3.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 3.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 4.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 4.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 5.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 6.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 6.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 7.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 7.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 8.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 9.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 9.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 10.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 10.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 11.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 12.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 12.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 13.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 13.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 14.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 15.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 15.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 16.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 16.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 17.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 18.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 18.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 19.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 19.8 mg / kg. In some embodiments, the siRNA is 101 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT administered at a one or more subsequent dose of about 20.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 21.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 21.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 22.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 22.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 23.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 24.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 24.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 25.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 25.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 26.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 27.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 27.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 28.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 28.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 29.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 30.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 30.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 31.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 31.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 32.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 33.0 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 33.6 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 34.2 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 34.8 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 35.4 mg / kg. In some embodiments, the siRNA is administered at a one or more subsequent dose of about 36.0 mg / kg.

[0191] In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg to about 60 mg / kg comprises the siRNA at a one or more 102 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT subsequent dose of about 0.6 mg / kg to about 36.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg, comprises the siRNA at a one or more subsequent dose of about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3.0 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.0 mg / kg, about 6.6 mg / kg, about 7.2 mg / kg, about 7.8 mg / kg, about 8.4 mg / kg, about 9.0 mg / kg, about 9.6 mg / kg, about 10.2 mg / kg, about 10.8 mg / kg, about 11.4 mg / kg, about 12.0 mg / kg, about 12.6 mg / kg, about 13.2 mg / kg, about 13.8 mg / kg, about 14.4 mg / kg, about 15.0 mg / kg, about 15.6 mg / kg, about 16.2 mg / kg, about 16.8 mg / kg, about 17.4 mg / kg, about 18.0 mg / kg, about 18.6 mg / kg, about 19.2 mg / kg, about 19.8 mg / kg, about 20.4 mg / kg, about 21.0 mg / kg, about 21.6 mg / kg, about 22.2 mg / kg, about 22.8 mg / kg, about 23.4 mg / kg, about 24.0 mg / kg, about 24.6 mg / kg, about 25.2 mg / kg, about 25.8 mg / kg, about 26.4 mg / kg, about 27.0 mg / kg, about 27.6 mg / kg, about 28.2 mg / kg, about 28.8 mg / kg, about 29.4 mg / kg, about 30.0 mg / kg, about 30.6 mg / kg, about 31.2 mg / kg, about 31.8 mg / kg, about 32.4 mg / kg, about 33.0 mg / kg, about 33.6 mg / kg, about 34.2 mg / kg, about 34.8 mg / kg, about 35.4 mg / kg, or about 36.0 mg / kg, respectively.

[0192] In some embodiments, the composition administered at a one or more subsequent dose of about 1 mg / kg comprises the siRNA at a one or more subsequent dose of about 0.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 2 mg / kg comprises the siRNA at a one or more subsequent dose of about 1.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 3 mg / kg comprises the siRNA at a one or more subsequent dose of about 1.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 4 mg / kg comprises the siRNA at a one or more subsequent dose of 103 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 2.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 5 mg / kg comprises the siRNA at a one or more subsequent dose of about 3.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 6 mg / kg comprises the siRNA at a one or more subsequent dose of about 3.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 7 mg / kg comprises the siRNA at a one or more subsequent dose of about 4.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 8 mg / kg comprises the siRNA at a one or more subsequent dose of about 4.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 9 mg / kg comprises the siRNA at a one or more subsequent dose of about 5.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 10 mg / kg comprises the siRNA at a one or more subsequent dose of about 6.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 11 mg / kg comprises the siRNA at a one or more subsequent dose of about 6.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 12 mg / kg comprises the siRNA at a one or more subsequent dose of about 7.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 13 mg / kg comprises the siRNA at a one or more subsequent dose of about 7.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 14 mg / kg comprises the siRNA at a one or more subsequent dose of about 8.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 15 mg / kg comprises the siRNA at a one or more subsequent dose of about 9.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 16 mg / kg comprises the siRNA at a one or more subsequent dose of about 9.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 17 mg / kg comprises the siRNA at a one or more subsequent dose of about 10.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 18 mg / kg comprises the siRNA at a one or more subsequent dose of about 10.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 19 mg / kg comprises the siRNA at a one or more subsequent dose of about 11.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 20 mg / kg comprises the siRNA at a one or more subsequent dose of about 12.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 21 mg / kg comprises the siRNA at a one or more subsequent dose of 104 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT about 12.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 22 mg / kg comprises the siRNA at a one or more subsequent dose of about 13.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 23 mg / kg comprises the siRNA at a one or more subsequent dose of about 13.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 24 mg / kg comprises the siRNA at a one or more subsequent dose of about 14.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 25 mg / kg comprises the siRNA at a one or more subsequent dose of about 15.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 26 mg / kg comprises the siRNA at a one or more subsequent dose of about 15.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 27 mg / kg comprises the siRNA at a one or more subsequent dose of about 16.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 28 mg / kg comprises the siRNA at a one or more subsequent dose of about 16.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 29 mg / kg comprises the siRNA at a one or more subsequent dose of about 17.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 30 mg / kg comprises the siRNA at a one or more subsequent dose of about 18.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 31 mg / kg comprises the siRNA at a one or more subsequent dose of about 18.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 32 mg / kg comprises the siRNA at a one or more subsequent dose of about 19.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 33 mg / kg comprises the siRNA at a one or more subsequent dose of about 19.8 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 34 mg / kg comprises the siRNA at a one or more subsequent dose of about 20.4 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 35 mg / kg comprises the siRNA at a one or more subsequent dose of about 21.0 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 36 mg / kg comprises the siRNA at a one or more subsequent dose of about 21.6 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of about 37 mg / kg comprises the siRNA at a one or more subsequent dose of about 22.2 mg / kg. In some embodiments, the composition administered at a one or more subsequent dose of ...

Claims

Attorney Docket No. ROO-039WO PATENT CLAIMS 1. A method of treating Pompe disease in a subject in need thereof, comprising: administering a composition comprising: an FN3 polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 6; and an oligonucleotide comprising: a sense strand comprising an oligonucleotide having the nucleic acid sequence that is at least 90% identical, to SEQ ID NO: 8, or a modified version thereof; and an antisense strand comprising an oligonucleotide having the nucleic acid sequence that is at least 90% identical to SEQ ID NO: 9, or a modified version thereof, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule, and wherein the amount of the oligonucleotide that is administered is at a dose of about 0.6 mg / kg to about 36.0 mg / kg.

2. The method of claim 1, wherein the FN3 polypeptide comprises the amino acid sequence SEQ ID NO:

6.

3. The method of claim 1, wherein the sense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 8, or a modified version thereof.

4. The method of claim 1, wherein the antisense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 9, or a modified version thereof.

5. The method of claim 1, wherein the sense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 8, or a modified version thereof and the antisense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 9, or a modified version thereof.

6. The method of claim 1, wherein the oligonucleotide comprises a nucleotide comprising a modification selected from the group consisting of: a 2’-O-methyl modification, 210 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 2’-deoxy modification, 2’-fluoro modification, a 2’-deoxy-2’-fluoro modification, a 2’-O- methoxyethyl (2’-O-MOE) modification, a 2’-O-aminopropyl modification,a 2’-O- aminopropyl (2’-O-AP) modification, a 2’- O-dimethylaminoethyl (2’-O-DMAOE) modification, a 2’-O-dimethylaminopropyl (2’-O-DMAP) modification, a 2’-O- dimethylaminoethyloxyethyl (2’-O-DMAEOE) modification, a 2’-O-N-methylacetamido (2’- O-NMA) modification, a locked nucleic acid (LNA) modification, a 2’-O,4’-C-Ethylene- bridge nucleic acid (ENA) modification, a peptide nucleic acid (PNA) modification, a hexitol nucleic acid modification, a morpholino modification, a phosphorothioate (PS) modification, a phosphorodithioate modification, a phosphonate modification, a vinyl phosphonate modification, 2’-O methyl vinlyl phosphonate modification, a thiolphosphonate modification, a methylphosphonate modification, a phosphoramidate modification, a mesyl phosphoramidate modification, a methyl phosphoramidate modification, and a 2’-fluoro N3- P5’-phosphoramidite modification, and a combination thereof.

7. The method of claim 6, wherein the sense strand oligonucleotide comprises a nucleic acid sequence that is at least 90% identical to SEQ ID NO:

10.

8. The method of claim 6, wherein the sense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO:

10.

9. The method of claim 6, wherein the antisense strand oligonucleotide comprises the nucleic acid sequence that is at least 90% identical to SEQ ID NO:

11.

10. The method of claim 5, wherein the modified sense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 10 and the modified antisense strand oligonucleotide comprises the nucleic acid sequence of SEQ ID NO:

11.

11. A method of treating Pompe disease in a subject in need thereof, comprising: administering a composition comprising: an FN3 polypeptide comprising an amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6; and an siRNA oligonucleotide comprising: a sense strand comprising a modified oligonucleotide having the nucleic acid sequence of SEQ ID NO: 10; and 211 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT an antisense strand comprising a modified oligonucleotide having the nucleic acid sequence of SEQ ID NO: 11, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule, and wherein the composition is administered to the subject at a dose of about 1 mg / kg to about 60 mg / kg.

12. The method of claim 1, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1 conjugated to the sense strand, wherein the linker molecule (L1) is selected from the group consisting of: O O O O O P N N 6), wherein L1O O O O O O O (PEG) bond to theO O O O O (iii) or Aminohexyl linker- bond to the siRNA; or,212 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 13. The method of claim 11, wherein the FN3 polypeptide and the oligonucleotide are linked via a linker molecule L1 conjugated to the sense strand, wherein the linker molecule (L1) is selected from the group consisting of: O O O O O P N N 6), wherein L1O O O O O O O P N O N N (PEG) bond to theO O O O O (iii) or Aminohexyl linker- bond to the siRNA; or,14. The method of claim 12, the sense strand modified oligonucleotide comprises the nucleic acid sequence of SEQ ID NO:

12.

15. The method of claim 13, the sense strand modified oligonucleotide comprises the nucleic acid sequence of SEQ ID NO:

12. 213 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 16. The method of 12, wherein the antisense modified oligonucleotide further comprises a vinyl phosphonate modification.

17. The method claim 16, wherein the antisense modified oligonucleotide has the nucleic acid sequence of SEQ ID NO:

13.

18. The method of 13, wherein the antisense modified oligonucleotide further comprises a vinyl phosphonate modification.

19. The method of claim 18, wherein the antisense modified oligonucleotide has the nucleic acid sequence of SEQ ID NO:

13.

20. The method of claim 1, wherein: the sense strand comprises the modified oligonucleotide having the nucleic acid sequence of SEQ ID NO: 12; and the antisense strand comprises the modified oligonucleotide having the nucleic acid sequence of SEQ ID NO:

13.

21. The method of claim 11, wherein: the sense strand comprises the modified oligonucleotide having the nucleic acid sequence of SEQ ID NO: 12; and the antisense strand comprises the modified oligonucleotide having the nucleic acid sequence of SEQ ID NO:

13.

22. The method of claim 1, wherein the composition has the formula of: siRNA-L1-F1, wherein: F1 is the FN3 domain; L1 is the linker; and siRNA is the oligonucleotide comprising the sense strand and the antisense strand.

23. The method of claim 22, wherein the siRNA-L1- F1 has a formula selected from: 214 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT24. The method of claim 22, wherein the siRNA-L1- F1 has a formula selected from Formula VI (top) or Formula VII (bottom): .

25. The method of claim 22, wherein F1 is conjugated to L1 through the cysteine at position 54 of SEQ ID NO:

6. 215 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT 26. The method of any one of claims 1-25, wherein the siRNA reduces the expression of GYS1 mRNA and reduces the expression of the GYS1 protein in the subject.

27. The method of any one of claims 1-25, wherein the subject has a decrease in GYS1 mRNA levels in skeletal muscle, compared to baseline, after administration has ceased for at least 4 weeks.

28. The method of any one of claims 1-25, wherein the subject has a decrease in GYS1 protein levels in skeletal muscle, compared to baseline, after administration has ceased for at least 4 weeks.

29. The method of any one of claims 1-25, wherein the subject has a decrease in glycogen levels in skeletal muscle, compared to baseline, after administration has ceased for at least 4 weeks.

30. The method of any one of claims 1-25, wherein the composition is administered at a dose that delivers a dose of the oligonucleotide that is about 6 mg / kg, about 12 mg / kg, or about 18 mg / kg.

31. The method of claim 30, wherein the composition is administered about every 4 weeks.

32. The method of any one of claims 1-31, wherein the composition is administered by an intravenous, a subcutaneous, or an intramuscular administration.

33. The method of any one of claims 1-25, wherein the administration of the composition results in an improvement in one or more clinical activity scores in the subject.

34. The method of any one of claims 1-25, wherein the subject has a improvement in the one or more clinical activity scores after administration has ceased for at least 4 weeks.

35. The method of any one of claims 1-25, wherein the administration of the composition results in an improvement in one or more clinical activity scores in the subject, wherein the improvement in the one or more clinical activity scores is an improvement in: hypernasality, 216 IPTS / 128947592.1Attorney Docket No. ROO-039WO PATENT speech intelligibility, dependency on invasive ventilation, cardiac status, motor function, or pulmonary function.

36. The method of any one of claims 1-25, wherein the administration of the composition results in an improvement in one or more clinical activity scores in the subject, wherein the improvement in the one or more clinical activity scores is an improvement in forced vital capacity (FVC) at sitting position, forced vital capacity (FVC) at standing position, gross motor function measure-88 (GMFM-88), left ventricular mass Z-score (LVM-Z), Kaplan- Meier estimate of survival rate, Kaplan-Meier estimate of invasive ventilator-free survival rate, quality of life (QoL) measurement, and / or 6-minute walk test score.

37. The method of any one of claims 1-25, wherein the subject has a decrease in any one, or any combination of: anti-recombinant human acid α-glucosidase (anti-rhGAA) antibody titers, compared to baseline, after administration has ceased for at least 4 weeks; serum creatine kinase, compared to baseline, after administration has ceased for at least 4 weeks; glycogen levels, compared to baseline, after administration has ceased for at least 4 weeks; creatinine levels, compared to baseline, after administration has ceased for at least 4 weeks; or Hex4 levels, compared to baseline, after administration has ceased for at least 4 weeks.

38. The method of any one of claims 1-25, wherein the administration results in reduced use of recombinant human acid α-glucosidase (anti-rhGAA) by the subject, after administration of the composition has ceased for at least 4 weeks. 217 IPTS / 128947592.1

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