Compositions and methods for treating cancer

Abstract

A double-stranded RNA interference (RNAi) agent comprising at least one of: (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting expression of a CD320 gene, wherein the first dsRNA comprises a sense strand and an antisense strand that form a duplex, (ii) a second dsRNA for inhibiting expression of an LRP2 gene, wherein the second dsRNA comprises a sense strand and an antisense strand that form a duplex, or (iii): a mixture of (i) and (ii), and wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA, and use of the RNAi agent as a pharmaceutical composition for treating cancer in a subject in need of treatment.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 62 / 785,592, filed on December 27, 2018, entitled “Compositions and Methods for Treating Cancer,” and the specification and claims of which are incorporated herein by reference.

[0003] Sequence Listing

[0004] This application contains a sequence listing filed electronically in ASCII format and incorporated herein by reference in its entirety. The ASCII copy, created on December 17, 2019, is named 32064-1035-PCT_SL.txt and is 374,821 bytes in size. Background Art

[0005] There are multiple cancer therapies and treatments, such as surgical resection, radiotherapy and chemotherapy of solid tumors. Although surgical resection and radiotherapy have been used for local tumors, chemotherapy is usually delivered systemically and affects both cancer and non-cancerous cells, resulting in serious and even life-threatening side effects. Earlier cancer drugs, including alkylating agents, nucleotide antimetabolites and tubulin poisons, have caused significant side effects because their toxicity to normal cells is similar to that to cancer cells, particularly those normal cells that undergo conventional cell division in the intestine, scalp and skin. For this reason, most of the work of modern cancer drug discovery is dedicated to finding targeted therapeutic agents (Neidle et al., (2014) Cancer Drug Design and Discovery) that distinguish cancer cells from normal cells. This has led to the production of drugs that suppress mutations, overexpression or abnormally high activity in cancer, but do not have the function of oncolytic proteins of the above characteristics in normal cells. Examples of these drugs include kinase inhibitors, histone deacetylase inhibitors, proteasome inhibitors, mTOR inhibitors, BCL2 inhibitors and isocitrate dehydrogenase inhibitors. A large amount of work is also dedicated to targeting cell surface antigens that are differentially expressed in cancer cells compared to normal cells. Therefore, monoclonal antibodies and antibody-drug conjugates targeting cancer cell surface antigens have been developed as cancer therapeutic agents (Beck et al., (2017) Nat Rev Drug Disc 16, 315-337). Another difference between cancer cells and normal cells is metabolism. Many years ago, it was found that, in contrast to the oxidative phosphorylation process used by normal cells, a variety of cancer cells use glucose fermentation to produce ATP. Recently, the FDA approved drugs targeting isocitrate dehydrogenase involved in abnormal glucose metabolism in cancer cells (Dhillon (2018) Drugs 78, 1509-1516). Abnormalities in single-carbon metabolism that cover the folic acid and methionine cycles and affect nucleotide synthesis and DNA methylation as a way to control gene expression are strongly associated with some cancers (Fanidi et al., (2019) Int J Cancer 145, 1499-1503; Yang (2018) Front Oncol 8, 493). In this regard, it has long been known that certain synthetic analogs of folic acid (antifolates) can inhibit the growth of cancer cells. It is also known that some cancer cells depend on the amino acid methionine for survival. If methionine is restricted, cancer cells die, although this has little effect on normal cells. In recent years, some signs have begun to emerge that some cancer cells may have an abnormal dependence on vitamin B12. The nature of this dependence is not yet understood, but it may be partly related to the use of vitamin B12 as a catalytic cofactor in one-carbon metabolism by the enzyme methionine synthase.

[0006] Vitamin B12 (cobalamin) is an essential micronutrient in the human diet. It is a cofactor for the metabolic enzymes methionine synthase and methylmalonyl-CoA mutase (Fedosov et al., (2012) Water Soluble Vitamins (book) 56, 347-367). After oral ingestion and enteral transport, cobalamin is almost completely bound to the chaperone proteins transcobalamin 1 (TCN1, haptocorrin, R-binding protein) (TCO1_HUMAN) and transcobalamin 2 (TCN2) (TCO2_HUMAN) in plasma. Most cells use receptor-mediated endocytosis to absorb the TCN2-cobalamin complex (TCN2-Cbl), and its plasma half-life is 1-15 hours. TCN2 has high affinity and specificity for cobalamin in its various dietary and nutritional supplement forms, such as methylcobalamin, adenosylcobalamin, and cyanocobalamin (Fedosov et al., (2007) Biochem 46, 6446-6458). TCN1 is a glycoprotein present in two different forms in plasma (Marzolo and Farfan (2011) Biol Res 44, 81-105). The most abundant form is sialylated and has a plasma half-life of approximately 10 days (Bor (2004) Clin Chem 50, 1043-1049). The less abundant form is desialylated and has a plasma half-life of several minutes. Unlike TCN2-Cbl, which can be taken up by almost all cell types, the transcobalamin protein 1-cobalamin complex (TCN1-Cbl), only in its desialylated form, is rapidly taken up by certain hepatocytes through receptor-mediated endocytosis.

[0007] CD320 and LRP2 are two receptors involved in the absorption of cobalamin as TCN2-Cbl. CD320 is a member of the low-density lipoprotein receptor (LDLR) family. It is constitutively expressed in most cells and is the receptor primarily responsible for cobalamin absorption (Quadros (2013) Biochimie 95, 1008-1018). CD320 is overexpressed in some cancer types (Sycel et al., (2013) Anticancer Res 33, 4203-4212; Amagasaki (1990) Blood 76, 1380-1386). There is also evidence that CD320 facilitates the transport of TCN2-Cbl to the brain through the blood-brain barrier (Lai et al; (2013) FASEB 27, 2468-2475). LRP2 is another receptor in the LDLR family. It is most highly expressed in the kidney, but is also expressed in other tissues. In addition to cobalamin, LRP2 also transports a variety of proteins and small molecules, including albumin, insulin, and vitamin D (Mazolo et al., (2011) Biol Res 44, 89-105). In the liver, as long as TCN1 is in its desialylated form, the asialoglycoprotein receptor (ASGR) takes up TCN1-Cbl through receptor-mediated endocytosis. Normal hepatocytes and hepatoma cells express extremely high levels of ASGR (~50,000 receptors per cell), making this receptor an attractive entry point for drug delivery to the liver (Luo et al., (2017) Biomedicine and Pharmacotherapy 88, 87-94; Stockert (1995) Physiological Rev 75, 595-609; Soda et al., Blood (1985) 65, 795-802).

[0008] Following receptor-mediated endocytosis, cobalamin is sequestered in endosomes, where the endosomal membrane prevents passive efflux to the cytosol. A specialized protein (cblF) facilitates cobalamin transport across the endosomal membrane to the cytosol (Banerjee et al., (2009) Curr Opin Chem Bio 13, 484-491). Summary of the Invention

[0009] One embodiment of the present invention provides a double-stranded RNA interference (RNAi) agent comprising at least one of: (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting CD320 gene expression, wherein the first dsRNA comprises a sense strand and an antisense strand that form a duplex, (ii) a second dsRNA for inhibiting LRP2 gene expression, wherein the second dsRNA comprises a sense strand and an antisense strand that form a duplex, or (iii) a mixture of (i) and (ii), wherein the sense strand of the first dsRNA is at least substantially complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is at least substantially complementary to the antisense strand of the second dsRNA. For example, (i) the antisense strand of the first dsRNA includes a region complementary to a CD320 RNA transcript, and (i) the sense strand of the first dsRNA is selected from Table 5. (ii) the antisense strand of the second dsRNA includes a region complementary to an LRP2 RNA transcript, and (ii) the sense strand of the second dsRNA is selected from Table 6. In one example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region of 16-30 nucleotide pairs in length. In another example, (i) the first dsRNA or (ii) the second dsRNA comprises a duplex region of 21-23 nucleotide pairs in length. In one embodiment, the double-stranded RNAi agent comprises at least one strand of the following: a 3' overhang comprising at least 2 nucleotides (i) the first dsRNA or (ii) the second dsRNA. In addition, in one embodiment, the antisense strand of (i) the first dsRNA comprises a nucleotide sequence selected from the following (5'→3'):

[0010] CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17);

[0011] CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT(SEQ ID NO 18);

[0012] mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU

[0013] mCdT*dT (SEQ ID NO 19);

[0014] mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU

[0015] mC (SEQ ID NO 21);

[0016] mCmAmGmUmUmGmCmGmCmAmGmUmUmUmCmUmUmGmUmCmAmGmUmU

[0017] mCdT*dT(SEQ ID NO 23);

[0018] mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fU

[0019] mCdT*dT(SEQ ID NO 24);

[0020] mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fU

[0021] mC(SEQ ID NO 25);

[0022] 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2fAmG2fUmU

[0023] 2fCdT*dT(SEQ ID NO 28);

[0024] 2fCmA2fGmU2fUmG2fCmG2fCmA2fGmU2fUmU2fCmU2fUmG2fUmC2fAmG2fUmU

[0025] 2fC(SEQ ID NO 29);

[0026] mC2fA2fG2fU2fU2fG2fC2fG2fC2fA2fG2fU2fU2fU2fC2fU2fU2fG2fU2fC2fA2fG2fU2fU

[0027] 2fCdT*dT(SEQ ID NO 30);

[0028] mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU2fUmCdT*dT(SEQ ID NO 32);

[0029] mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fUmU2fGmU2fCmA2fGmU(SEQ ID NO33);

[0030] mC2fAmG2fUmU2fGmC2fGmC2fAmG2fUmU2fUmC2fU2fU2fG2fU2fC2fA2fG2fU (SEQ IDNO 34);

[0031] wherein mA, mC, mG, and mU are 2'-O-methyladenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoroadenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate bond; and

[0032] The sense strand and the antisense strand are at least substantially complementary.

[0033] Furthermore, in another embodiment, the double-stranded RNAi agent comprises (i) an antisense strand of a first dsRNA, the antisense strand comprising a nucleotide sequence selected from the group consisting of (5'→3'):

[0034] AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64);

[0035] AAGAGCUCAGGUCUCUGAGGGdT*dT(SEQ ID NO 65);

[0036] mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmGdT*dT (SEQ ID NO 66);

[0037] mAmAmGmAmGmCmUmCmAmGmGmUmCmUmCmUmGmAmGmGmG (SEQ ID NO 68);

[0038] mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmGdT*dT (SEQ ID NO71);

[0039] mA2fAmG2fAmG2fCmU2fCmA2fGmG2fUmC2fUmC2fUmG2fAmG2fGmG (SEQ ID NO 72);

[0040] 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO75);

[0041] 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 76);

[0042] mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fG (SEQ ID NO 77);

[0043] mA2fA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO78);

[0044] 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fCmU2fGmA2fGmG2fGdT*dT (SEQ ID NO79);

[0045] 2fAmA2fGmA2fGmC2fUmC2fAmG2fGmU2fCmU2fC2fU2fG2fA2fG2fG2fG (SEQ ID NO81);

[0046] wherein mA, mC, mG, and mU are 2'-O-methyladenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoroadenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate bond; and

[0047] The sense strand and the antisense strand are at least substantially complementary.

[0048] In another embodiment, the double-stranded RNAi agent of (ii) the second dsRNA comprises a nucleotide sequence selected from the group consisting of (5'→3'):

[0049] UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417);

[0050] UUUGAUAGCACCAAACCUAGAGCCCdT*dT(SEQ ID NO:418);

[0051] mUm[mUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmC

[0052] dT*dT (SEQ ID NO: 419);

[0053] mUmUmUmGmAmUmAmGmCmAmCmCmAmAmAmCmCmUmAmGmAmGmCmCmC (SEQ ID NO: 421);

[0054] mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmCdT*dT] (SEQ ID NO: 424);

[0055] mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmC (SEQ IDNO: 425);

[0056] mU2fAmU2fCmA2fAmA2fCmC2fUmC2fGmA2fUmA2fGmC2fAmA2fCmA2fCmC2fGmC (SEQ IDNO: 429);

[0057] mU2fU2fU2fG2fA2fU2fA2fG2fC2fA2fC2fC2fA2fA2fA2fC2fC2fU2fA2fG2fA2fG2fC2fC2fCdT*dT(SEQ ID NO:430);

[0058] mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC2fCmCdT*dT (SEQ ID NO: 432);

[0059] mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fCmC2fUmA2fGmA2fGmC (SEQ ID NO: 433); and

[0060] mU2fUmU2fGmA2fUmA2fGmC2fAmC2fCmA2fAmA2fC2fC2fU2fA2fG2fA2fG2fC (SEQ IDNO: 434)

[0061] wherein mA, mC, mG, and mU are 2'-O-methyladenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoroadenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate bond; and

[0062] The sense strand and the antisense strand are at least substantially complementary.

[0063] In other embodiments, the antisense strand of the double-stranded RNAi agent of (ii) the second dsRNA comprises a nucleotide sequence selected from the group consisting of (5'→3'):

[0064] UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 448);

[0065] UUUGCAAUGACUCUCCUAUCAGUCCdT*dT(SEQ ID NO:449);

[0066] mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmCdT*dT (SEQ ID NO: 450);

[0067] mUmUmUmGmCmAmAmUmGmAmCmUmCmUmCmCmUmAmUmCmAmGmUmCmC (SEQ ID NO: 452);

[0068] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdT*dT (SEQ ID NO: 455);

[0069] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmC (SEQ IDNO: 456);

[0070] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fCmU2fC

[0071] mC (SEQ ID NO: 458);

[0072] 2fUmU2fUmG2fCmA2fAmU2fGmA2fCmU2fCmU2fCmC2fUmA2fUmC2fAmG2fUmC2fCdT*dT (SEQ ID NO: 459);

[0073] mU2fAmU2fCmC2fUmA2fAmG2fUmC2fAmC2fAmC2fGmU2fUmU2fGmA2fCmU2fGmC (SEQ IDNO: 460);

[0074] mU2fU2fU2fG2fC2fA2fA2fU2fG2fA2fC2fU2fC2fU2fC2fC2fU2fA2fU2fC2fA2fG2fU2fC2fCdT*dT(SEQ ID NO:461);

[0075] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU2fCmCdT*dT (SEQ ID NO: 463);

[0076] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fCmU2fAmU2fCmA2fGmU (SEQ ID NO: 464);

[0077] mU2fUmU2fGmC2fAmA2fUmG2fAmC2fUmC2fUmC2fC2fU2fA2fU2fC2fA2fG2fU(SEQ IDNO:465)

[0078] wherein mA, mC, mG, and mU are 2'-O-methyladenosine, cytidine, guanosine, or uridine, respectively; 2fA, 2fC, 2fG, and 2fU are 2'-fluoroadenosine, cytidine, guanosine, or uridine, respectively; and * is a phosphorothioate bond; and

[0079] The sense strand and the antisense strand are at least substantially complementary.

[0080] For example, when the RNAi agent comprises (iii): a combination of (i) a first dsRNA and (ii) a second dsRNA, the antisense strand of (i) the first dsRNA is selected from:

[0081] CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17);

[0082] CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT(SEQ ID NO 18);

[0083] AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64); and

[0084] AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65); and

[0085] (ii) the antisense strand of the second dsRNA is selected from:

[0086] UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417);

[0087] UUUGAUAGCACCAAACCUAGAGCCCdT*dT(SEQ ID NO:418);

[0088] UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 448); and

[0089] UUUGCAAUGACUCUCCUAUCAGUCCdT*dT(SEQ ID NO:449);

[0090] wherein * is a phosphorothioate bond; and

[0091] The sense strand and the antisense strand are at least substantially complementary.

[0092] In one embodiment, (i) the first dsRNA has a duplex structure of (SEQ ID NOs: 17 and 110) or (SEQ ID NOs: 18 and 111). In another embodiment, (ii) the second dsRNA has a duplex structure of (SEQ ID NOs: 417 and 808) or (SEQ ID NOs: 448 and 822).

[0093] Another embodiment provides an isolated cell comprising the double-stranded RNAi agent of (i), (ii), or (iii).

[0094] For example, (i) the sense strand of the first dsRNA is no more than 30 nucleotides in length, and (ii) the antisense strand of the first dsRNA is no more than 30 nucleotides in length. For example, (ii) the sense strand of the second dsRNA is no more than 30 nucleotides in length, and the antisense strand is no more than 30 nucleotides in length.

[0095] Another embodiment provides a pharmaceutical composition for inhibiting CD320 gene expression, the pharmaceutical composition comprising the double-stranded RNAi agent (i) or (iii). In addition, the pharmaceutical composition may comprise an excipient.

[0096] Another embodiment provides a pharmaceutical composition for inhibiting LRP2 gene expression, the composition comprising a double-stranded RNAi agent (ii) or (iii). In addition, the pharmaceutical composition may comprise an excipient.

[0097] Another embodiment of the present invention provides a method for inhibiting cancer cell (CC) proliferation, comprising contacting CC with an inhibitor of CD320 and / or LRP2 in an amount effective to inhibit CC proliferation. For example, CC may express CD320 and / or LRP2 or both.

[0098] Another embodiment of the invention provides a method of treating a therapy-resistant cancer in a subject who has previously received therapy, comprising administering to the subject an inhibitor of CD320 and / or LRP2 in an amount effective to inhibit or kill cancer cells (CCs) present in the therapy-resistant cancer.

[0099] Another embodiment of the present invention provides a method for treating cancer in a subject having relapsed or recurrent cancer, comprising administering to the subject an inhibitor of CD320 and / or LRP2 in an amount effective to inhibit or kill CC in the cancer.

[0100] The CCs are from a cancer selected from the group consisting of melanoma, glioblastoma, lung cancer, breast cancer, triple negative breast cancer, hepatocellular carcinoma, kidney cancer, pancreatic cancer, ovarian cancer, and prostate cancer.

[0101] The CD320 inhibitor is selected from an antibody that binds to CD320, a small molecule inhibitor of CD320, and an RNAi agent that hybridizes to a nucleic acid sequence encoding CD320.

[0102] Additionally, methods for inhibiting CC proliferation and treating treatment-resistant cancer in subjects with recurrent or recurrent cancer include administering a cancer therapeutic agent in combination with an RNAi agent that hybridizes to mRNA encoding CD320 or an RNAi agent that hybridizes to mRNA encoding LRP2. For example, the cancer therapeutic agent is selected from antifolates, epigenetic regulators, or small molecule or protein inhibitors of CD320 function or LRP2 function, such as antibodies to CD320 or LRP2. Additionally, the method further includes administering metformin. For example, the RNAi agent includes the antisense strand of Table 5 or Table 6.

[0103] The inhibitor is selected from an antibody that binds to LRP2, a small molecule inhibitor of LRP2, and an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2. For example, the method further comprises administering a cancer therapeutic agent selected from the group consisting of antifolates, epigenetic regulators, or small molecule or protein inhibitors of LRP2 function, such as antibodies, in conjunction with an RNAi agent that hybridizes to an mRNA encoding LRP2.

[0104] The method further comprises administering a cancer therapeutic agent in conjunction with an RNAi agent that hybridizes to the mRNA encoding LRP2.

[0105] One embodiment of the present invention provides a method for inhibiting cancer cell (CC) proliferation, comprising contacting the CC with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in amounts effective to inhibit CC proliferation. For example, the composition is a mixture comprising: i) a CD320 inhibitor selected from an antibody that binds to CD320, a small molecule inhibitor of CD320, an RNAi agent that hybridizes to a nucleic acid sequence encoding CD320, and any combination thereof; and ii) an LRP2 inhibitor selected from an antibody that binds to LRP2, a small molecule inhibitor of LRP2, an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2, and any combination thereof. Additionally, the method further comprises administering a cancer therapeutic agent selected from the group consisting of antifolates and epigenetic regulators. For example, an RNAi agent that hybridizes to an mRNA encoding CD320 comprises a first double-stranded RNA (dsRNA) for inhibiting CD320 expression, wherein the first dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region complementary to a CD320 RNA transcript, and an RNAi agent that hybridizes to an mRNA encoding LRP2 comprises a second dsRNA for inhibiting LRP2 expression, wherein the second dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region complementary to a LRP2 RNA transcript. In another example, the antisense strand complementary to the CD320 RNA transcript is selected from Table 5, and the antisense strand complementary to the LRP2 RNA transcript is selected from Table 6. The method further comprises administering a cancer therapeutic selected from the group consisting of antifolates and epigenetic regulators. The method further comprises administering a cancer therapeutic selected from the group consisting of immunomodulators. Additionally, the method further comprises administering metformin.

[0106] One aspect of one embodiment of the present invention provides a method for inhibiting the expression of CD320 and LRP2 proteins, thereby reducing the levels of these proteins in treated cells compared to their endogenous levels in untreated cells; such inhibition may also be referred to as knockdown of CD320 and LRP2 expression. The method entails the use of a cocktail of small interfering RNA molecules, also known as siRNAs, that direct mRNA sequences encoding CD320 or LRP2 to an enzymatic complex that results in the targeted destruction of these mRNAs.

[0107] Another aspect of the present invention provides methods for inhibiting the expression of LRP2 and CD320 proteins, either alone or simultaneously, which inhibit the growth of various cancer cells compared to non-cancerous (normal) cells. In some cases, knocking down CD320 or LRP2 protein alone is sufficient to severely inhibit cancer cell proliferation compared to normal cells.

[0108] Another aspect of the present invention provides inhibition of cancer cell proliferation by inhibiting LRP2 receptor expression.

[0109] Mechanistic studies of the selective uptake of porphyrins by cancer cells have led to the generation of several unobvious compounds and methods of using the same. Knockdown of the expression of the CD320 gene or the LRP2 gene, or both, has been found to result in cell death or cell growth inhibition in a panel of lung cancer cell lines compared to normal fibroblasts. Figure 1 The experimental summary is shown. In these experiments, cells were plated on day 0. The next day (day 1), viral particles encoding short hairpin RNA (shRNA) against the CD320 gene and the LRP2 gene or an irrelevant shRNA control were added to the cell culture along with protamine sulfate, a reagent that facilitates cell entry of viral particles.

[0110] Further studies showed that knockdown of the CD320 gene or LRP2 gene expression, or simultaneous knockdown of the CD320 and LRP2 gene expression using small interfering RNA (siRNA), resulted in cell death or cell growth inhibition in a panel of cancer cell lines (including lung cancer, prostate cancer, breast cancer, glioblastoma, and melanoma) compared to normal fibroblasts (Figures 9-10). It was also found that knockdown of one gene, CD320 or LRP2, led to increased expression of the other in some cancer cell lines.

[0111] One aspect of the present invention provides for in vivo and in vitro knockdown of the CD320 receptor, the LRP2 receptor, or both in cancer cells expressing CD320 mRNA and / or LRP2 mRNA.

[0112] Another aspect of the invention is a method of inhibiting cell growth or causing cell death of cancer cells treated with a compound as described herein, while leaving normal cells unaffected or causing less cell growth inhibition or less cell death compared to cancer cells treated with the same amount of the compound.

[0113] Another aspect of the first compounds and methods of use is selective therapy that inhibits cancer cell proliferation and / or kills cancer cells through inhibition of the LRP2 receptor while leaving normal cells unharmed.

[0114] Another aspect of the second compounds and methods of use is selective therapy that inhibits cancer cell proliferation and / or kills cancer cells through inhibition of the CD320 receptor while leaving normal cells unharmed.

[0115] Another aspect of the invention provides cancer treatment for selectively inhibiting cancer cell proliferation and / or killing cancer cells by administering therapy using one or more of the following: a first compound that is an inhibitor of the CD320 receptor, a second compound that is an inhibitor of the LRP2 receptor, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the present invention. The accompanying drawings are only for the purpose of illustrating one or more embodiments of the present invention and should not be construed as limiting the present invention. In the drawings:

[0117] Figure 1 The experimental design for knocking down CD320 and LRP2 in cells is shown. On day 0, cells were plated. The next day (day 1), viral particles encoding short hairpin RNA (shRNA) or non-targeted shRNA controls for CD320 and LRP2 mRNA were added to the cell culture together with protamine sulfate, a reagent that facilitates cell entry of viral particles. Table 1 shows the sequences used. Each shRNA coding sequence is also combined with a unique drug resistance gene, which will enable the selection of those cells that have absorbed the shRNA; cells that have not absorbed the shRNA will not survive. On day 2, drug selection was started. On day 3, cells were harvested and plated in new culture dishes. Only cells with drug resistance genes, i.e. cells that have absorbed shRNA viral particles, will survive this re-plating procedure. From day 4 onwards, the growth of each cultured cell was observed closely. Cells infected with non-targeted negative control shRNA continued to grow - data not shown. The results of the cell lines expressing CD320+LRP2shRNA are shown in Table 1.

[0118] Figure 2A -C shows the sensitivity of cancer cell lines to CD320 and LRP2 knockdown. Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentivirus expressing control sequence or shCD320 and shLRP2 shRNA, as shown in Figure 5. Figure 1 Cell growth, as shown. Figure 1 As described. Cell photos were taken on day 9 after lentiviral transfection. The solid oval represents the healthy growth of normal fibroblasts infected with shRNA targeting CD320 and LRP2. The dotted oval represents the unhealthy dying cancer cells infected with shRNA targeting CD320 and LRP2 ( Figure 2A ).right Figure 2A Cell fields were counted and quantified in Figure 2B Displayed in Figure 2B The data in the were normalized to the number of control cells and Figure 2C Displayed in. Figure 2C It is shown that cell cultures infected with lentivirus encoding shRNAs for CD320 and LRP2 (white bars) contained far fewer cells than cell cultures exposed to shRNA controls (black bars).

[0119] Figure 3A -F shows graphs of protein levels resulting from transfection of HEK293, MDA-MB-435S, and MDA-MB-231 cells with siRNAs targeting LRP2 and CD320. HEK293, MDA-MB-435S, and MDA-MB-231 cells were transfected with 20 nM of the indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated as OSC17 and OSC47. siRNAs targeting LRP2 are designated as OSL245, OSL47, OSL104, OSL90, and OSL119. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. Protein levels were normalized to a housekeeping control gene that was unaffected by siRNA transfection. Figure 3A -F shows the fold change in protein levels compared to siScramble (OSS1 or OSS2). (Mean values + / - SEM are shown, n=3).

[0120] Figure 4A -F shows images of cells after transfection of LnCAP, MCF-7, and U251 cells with siRNAs targeting LRP2 and CD320. LnCAP, MCF-7, and U251 cells were transfected with 20 nM of the indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated as OSC17 and OSC47. siRNAs targeting LRP2 are designated as OSL245, OSL47, OSL104, OSL90, and OSL119. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. Protein levels were normalized to a housekeeping control gene that was unaffected by siRNA transfection. Figure 4A -F shows the fold change in protein levels compared to siScramble (OSS2).

[0121] Figure 5A -C shows graphs of protein levels after transfection of A172, DU145, and GM05659 cells with siRNA targeting LRP2 and CD320. A172, DU145, and GM05659 cells were transfected with 20 nM of the indicated siRNAs and incubated for 48 hours. siRNAs targeting CD320 are designated as OSC17 and OSC47. siRNAs targeting LRP2 are designated as OSL245, OSL47, OSL104, OSL90, and OSL119. Whole cell lysates were prepared and immunoblotted for CD320. Protein levels were normalized to a housekeeping control gene that was unaffected by siRNA transfection. Figure 5A -C shows the fold change in protein levels compared to siScramble(OSS2).

[0122] Figure 6 A graph showing relative LRP2 protein expression in various cell lines is shown - lysates were prepared from the cell lines indicated on the x-axis and immunoblotted to determine LRP2 protein levels. Results represent the mean + / - SEM of 3 independent lysates.

[0123] Figure 7A -B shows the effect of doxorubicin treatment on cell viability, as measured by CTG assay. A172 and HCC15 cells were plated in 96-well plates at 1200 cells / well. The next day, cells were treated with the indicated concentrations of doxorubicin. Four days after starting doxorubicin treatment, cell viability was determined using the CTG assay. The dashed line indicates the calculated IC 50 Nonlinear fit of the data.

[0124] Figure 8 Schematic diagram of a functional assay for screening the effects of siRNA on cell proliferation to facilitate quantitative knockdown of CD320 and LRP2 on cell proliferation. Cells were plated in 24-well plates. The next day, cells were transfected with siRNA targeting CD320 (OSC17, OSC47) and / or targeting LRP2 (OSL231, OSL245) or control siRNA (OSS2). For effective toxicity, cell lines may require repeated transfections and / or time (cell line dependent). In this experimental design, there is still room for repeated infection, and some cell lines should be required for effective toxicity. In addition, in a small subset of wells, cells were treated with doxorubicin as a positive control for toxicity. At the end of the study, cell growth of the cell lines was analyzed by CTG assay.

[0125] Figure 9A -E shows a graph of the percentage of cell survival for siCD320 and siLRP2 on cell proliferation - Representative cell lines of several cancer types (lung, brain) or normal fibroblasts were transfected with siRNA targeting CD320 (OSC17, OSC47) or LRP2 (OSL231, OSL245) alone or in combination (10 nM each) or with a negative control siRNA (OSS2) (20 nM) as indicated. For potent toxicity, cells were repeatedly transfected as listed in Table 9 and then viability was determined by CTG assay. In our assay, doxorubicin-treated cells were used as a positive control for cytotoxicity (Table 8).

[0126] Figure 10A-E shows the effect of siCD320 and siLRP2 on cell proliferation - Representative cell lines of several cancer types (breast, prostate, skin) were transfected with siRNA targeting CD320 (OSC17, OSC47) or LRP2 (OSL231, OSL245) alone or in combination as indicated. For effective toxicity, cells were repeatedly transfected as listed in Table 9 and then viability was determined by CTG assay. In our assay, doxorubicin-treated cells were used as a positive control for cytotoxicity (Table 8).

[0127] Figure 11A -B shows the effect of the siCD320 and siLRP2 molar ratios on cell proliferation by different molar ratios of siRNA targeting CD320 and siRNA targeting LRP2. As indicated, representative cell lines of two cancer types (breast, prostate) were transfected with different ratios of siRNA targeting CD320 (OSC17) or siRNA targeting LRP2 (OSL245) (0-20 nM) or with negative control siRNA (OSS2). For effective toxicity, cells were repeatedly transfected and then viability was determined by CTG assay. In our assay, doxorubicin-treated cells were used as a positive control for cytotoxicity (Table 8).

[0128] Figure 12A -B shows a graph of the duration of knockdown of MDA-MD-231 cells by siCD320 and siLRP2. On day 0, a representative breast cancer cell line (MDA-MD-231) was transfected with 20 nM siRNA targeting CD320 (OSC17) or siRNA targeting LRP2 (OSL245) or a negative control siRNA (OSS2), and the percentage of protein knockdown was analyzed daily by immunoblotting over a 5-day period. Protein levels were normalized to the negative control (OSS2).

[0129] Figure 13 This figure shows a poly(ethyleneimine) (PEI)-siRNA complex. PEI and siRNA are mixed together. The resulting polyplex (nanoparticle, broadly speaking) of the PEI-siRNA complex is then able to enter cells.

[0130] Figure 14Schematic diagram showing that siRNA is a short RNA double helix of usually 16 to 30 nucleotides; the guide sequence of siRNA is complementary to the mRNA expressed in the cell. Exogenous siRNA double helix is introduced into the cell by transfection. The siRNA double helix is separated by the RISC / AGO (RNA-induced silencing complex) complex, so that the guide strand of the siRNA hybridizes with its complementary mRNA molecule. By having RNase activity, the RISC / AGO complex that causes mRNA degradation degrades the mRNA and does not produce the protein encoded by the mRNA. Compared to control treated cells, this results in a "knockdown" effect or reduced protein level of the gene targeted by the siRNA.

[0131] Figure 15A -B shows a graph of A172 cell lines or MDA-MD-435S cell lines treated with control siRNA (OSS1, OSS2) and siRNA against CD320 mRNA (OSC17, OSC47) and LRP2 mRNA (OSL231, OSL245) to determine the effectiveness of INTERFERin, a polyethanolamine transfection reagent, in delivering siRNA to cancer cells.

[0132] Figure 16A -D shows plated cells showing the effects of siCD320 and siLRP2 on four cell lines. Representative cell lines of four cancer types (breast, two prostate, skin) were transfected with siRNA targeting CD320 (OSC17) or siRNA targeting LRP2 (OSL245) alone at 20 nM or in combination (10 nM each), or with negative control siRNA (OSS2) (20 nM), as indicated. Cells were repeatedly transfected for effective toxicity as in Table 9 and then analyzed by microscopy as indicated.

[0133] Figure 17 A graphical representation of CD320 mRNA is shown. UTR indicates untranslated region, and CDS indicates protein coding sequence.

[0134] Figure 18 A graphical representation of LRP2 mRNA is shown. UTR indicates untranslated region, and CDS indicates protein coding sequence.

[0135] Figure 19A -G shows the structure of a non-natural nucleotide that can be introduced into the RNAi sequence."B" represents a natural (G, C, A, U) RNA nucleobase, a DNA nucleobase, or a non-natural nucleobase. Figure 19A Certain chemical modifications to the ribose 2'-position and the phosphate moiety are shown. Figure 19B -D shows a backbone modification to the ribose moiety including a bridging group. Figure 19E The absence of the C2'-C3' bond is shown. Figure 19F -G shows an additional backbone modification to the ribose moiety, where a six-membered ring replaces the five-membered ring.

[0136] Figure 20 A schematic diagram of an in vivo murine xenograft model of breast cancer is shown. MDA-MB-231 cells were implanted into the flank of NSG mice and grown to a volume of 70 mm. 3 , and then siRNA targeting CD320 (OSC17) and siRNA targeting LRP2 (OSL245) were injected intratumorally every 4 days. DETAILED DESCRIPTION

[0137] One or more embodiments of the present invention provide methods and RNAi compounds for regulating the expression of the CD320 gene and / or the LRP2 gene in cells. In certain embodiments, CD320- and / or LRP2-specific RNAi reduces or inhibits the expression of the CD320 gene and / or the LRP2 gene. Such inhibition can be useful for treating conditions such as cancer and / or generating cell lines useful for screening drugs for treating cancer.

[0138] The present invention also relates to methods for knocking down (partially or completely) a target gene.

[0139] One embodiment of the method for producing knockdown cells and organisms comprises introducing into a cell or organism in which a gene (referred to as a target gene) is to be knocked down an siRNA of about 16 to about 30 nucleotides (nt) targeting the gene and maintaining the resulting cell or organism under conditions where RNAi occurs, thereby causing degradation of the mRNA of the target gene, thereby producing the knockdown cell or organism. The knockdown cells and organisms produced by the methods of the present invention are also the subject of embodiments of the present invention.

[0140] Embodiments of the present invention also relate to methods for checking or evaluating the function of a gene in a cell or an organism. In one embodiment, an RNA of about 16 to about 30nt of the mRNA of a gene targeted for degradation is introduced into a cell or organism in which RNAi occurs. This cell or organism is referred to as a test cell or organism. This cell or organism is referred to as a test cell organism. This test cell or organism is maintained under the condition that the mRNA of the gene is degraded. Then, the phenotype of the test cell or organism is observed and compared with the phenotype of the corresponding cell or organism processed in the same manner, such as except not targeting this gene. 16 to 30nt RNA of the mRNA not targeted for degradation can be introduced into control cells or organism to replace the siRNA introducing the test cell or organism, although it is not necessary to do so. The difference between the test and control cell or biological phenotype provides information about the function of the mRNA of the degradation.

[0141] The RNA of about 16 to about 30 nucleotides is separated or synthesized and then introduced into the cell or biology (test cell or test biology) in which RNAi occurs. Test cell or test biology is maintained under the condition that mRNA is degraded. Then, observe test cell or biological phenotype and with appropriate control, as except not targeting target gene, with the corresponding cell of test cell or biological identical mode processing or biological phenotype compared. The difference between test and control cell or biological phenotype provides the information of the function of relevant target gene. The information provided can be enough to identify the function of (limiting) gene or can be used in conjunction with the information that derives from other mensuration or analysis of doing so.

[0142] Embodiments of the present invention also encompass methods of treating a disease or condition associated with the presence of a protein in an individual, comprising administering to the individual an RNA of about 16 to about 30 nucleotides that targets the mRNA of the protein for degradation (mRNA encoding the protein). Thus, the protein is not produced, or is not produced to the extent that treatment would not be present.

[0143] Figure 14 siRNA is a short RNA double helix of usually 16 to 30 nucleotides; The sequence of siRNA is complementary to the mRNA expressed in the cell. Exogenous siRNA double helix is introduced into the cell by transfection. The siRNA double helix is unwound by the RNA-induced silencing complex (RISC), so that the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC / AGO complex, which has RNase cleavage activity. The end result is that the mRNA targeted by the siRNA is degraded and the protein encoded by the mRNA is not produced. Compared with the control treated cells, this results in a "knock-down" effect or reduced protein level of the gene targeted by the siRNA.

[0144] In one embodiment, at least one chain of the RNA molecule has a 3' overhang of about 1 to about 6 nucleotides (e.g., pyrimidine nucleotides, purine nucleotides) in length. In other embodiments, the 3' overhang is about 1 to about 5 nucleotides, about 1 to about 3 nucleotides and about 2 to about 4 nucleotides in length, or, for example, if the guide strand is a 27-mer, the overhang can be as many as 14 nucleotides. In one embodiment, the RNA molecule is double-stranded, one chain has a 3' overhang and the other chain can be a sticky end or have an overhang. In embodiments where the RNA molecule is double-stranded and the two chains comprise an overhang, the length of the overhang can be the same or different for each chain. In a specific embodiment, the RNA of the present invention comprises a chain of 21-27 nucleotides, which is Watson-Crick paired and has an overhang of about 1 to about 3, specifically about 2 nucleotides at the two 3' ends of the RNA. In order to further improve the stability of the RNA of the present invention, the 3' overhang can be stabilized relative to degradation. In one embodiment, the RNA is stabilized by including purine nucleotides, such as adenosine or guanosine nucleotides. Alternatively, the replacement of pyrimidine nucleotides by non-natural nucleotides, for example, the replacement of uridine 2 nucleotide 3' overhangs by 2'-deoxythymidine, is tolerated without affecting the efficiency of RNAi. The absence of the 2' hydroxyl group significantly improves the nuclease tolerance of the overhang in tissue culture medium. The 3'-overhang can be further stabilized by introducing a phosphorothioate group instead of a phosphodiester.

[0145] The 16-30 nt RNA molecules of the present invention can be obtained using some techniques known to those skilled in the art. For example, RNA can be chemically synthesized or recombinantly produced using methods known in the art.

[0146] In order that the present invention may be more readily understood, certain terms are first defined. Additionally, it should be noted that whenever a parameter value or range of values is recited, it is intended that values and values intermediate to the recited range of values are also intended to be part of the present invention.

[0147] The articles "a" and "an" are used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element, for example, a plurality of elements.

[0148] The term "comprising" is used herein to mean, and is interchangeable with, the phrase "including, but not limited to."

[0149] Unless the context clearly indicates otherwise, the term "or" is used herein to mean, and is interchangeable with, the term "and / or."

[0150] As used herein, "CD320" refers to a gene or protein. CD320 is also known as 8D6 antigen, CD320 antigen, 8D6A, cobalamin transducer receptor, FDC-SM-8D6, FDC-signaling molecule 8D6, 8D6, TCBLR, TCblR, TCN2R. The term CD320 includes human CD320, whose amino acid and nucleotide sequences can be found, for example, in Genbank Accession Nos. NM_016579.4 and NM_001165895.2; mouse CD320, whose amino acid and nucleotide sequences can be found, for example, in Genbank Accession No. NM_019421.3; and rat CD320, whose amino acid and nucleotide sequences can be found, for example, in Genbank Accession No. NM_001014201.1. Other examples of CD320 mRNA sequences are readily available using, for example, GenBank. Additional information is found at Figure 17 .

[0151] The CD320 mRNA sequence from Homo sapiens is shown below: >NM_016579.4 Homo sapiens CD320 molecule (CD320), transcript variant 1, DNA

[0152] GTGCGCGTGCGCAGGGATAAGAGAGCGGTCTGGACAGCGCGTGGCCGGCGCCGCTGTGGGGACAGCATGA

[0153] GCGGCGGTTGGATGGCGCAGGTTGGAGCGTGGCGAACAGGGGCTCTGGGCCTGGCGCTGCTGCTGCTGCT

[0154] CGGCCTCGGACTAGGCCTGGAGGCCGCCGCGAGCCCGCTTTCCACCCCGACCTCTGCCCAGGCCGCAGGC

[0155] CCCAGCTCAGGCTCGTGCCCACCCACCAAGTTCCATGCCGCACCAGTGGCTTATGCGTGCCCCTCACCT

[0156] GGCGCTGCGACAGGGACTTGGACTGCAGCGATGGCAGCGATGAGGAGGAGTGCAGGATTGAGCCATGTAC

[0157] CCAGAAAGGGCAATGCCCACCGCCCCCTGGCCTCCCCTGCCCCTGCACCGGCGTCAGTGACTGCTCTGGG

[0158] GGAACTGACAAGAAACTGCGCAACTGCAGCCGCCTGGCCTGCCTAGCAGGCGAGCTCCGTTGCACGCTGA

[0159] GCGATGACTGCATTCCACTCACGTGGCGCTGCGACGGCCACCCAGACTGTCCCGACTCCAGCGACGAGCT

[0160] CGGCTGTGGAACCAATGAGATCCTCCCGGAAGGGGATGCCACAACCATGGGGCCCCCTGTGACCCTGGAG

[0161] AGTGTCACCTCTCTCAGGAATGCCACAACCATGGGGCCCCCTGTGACCCTGGAGAGTGTCCCCTCTGTCG

[0162] GGAATGCCACATCCTCCTCTGCCGGAGACCAGTCTGGAAGCCCAACTGCCTATGGGGTTATTGCAGCTGC

[0163] TGCGGTGCTCAGTGCAAGCCTGGTCACCGCCACCCTCCTCCTTTTGTCCTGGCTCCGAGCCCAGGAGCGC

[0164] CTCCGCCCACTGGGGTTACTGGTGGCCATGAAGGAGTCCCTGCTGCTGTCAGAACAGAAGACCTCGCTGC

[0165] CCTGAGGACAAGCACTTGCCACCACCGTCACTCAGCCCTGGGCGTAGCCGGACAGGAGGAGAGCAGTGAT

[0166] GCGGATGGGTACCCGGGCACACCAGCCCTCAGAGACCTGAGCTCTTCTGGCCACGTGGAACCTCGAACCC

[0167] GAGCTCCTGCAGAAGTGGCCCTGGAGATTGAGGGTCCCTGGACACTCCCTATGGAGATCCGGGGAGCTAG

[0168] GATGGGGAACCTGCCACAGCCAGAACTGAGGGGCTGGCCCCAGGCAGCTCCCAGGGGGTAGAACGGCCCT

[0169] GTGCTTAAGACACTCCTGCTGCCCCGTCTGAGGGTGGCGATTAAAGTTGCTTCACATCCTCAAAAAAAAA

[0170] AAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO. 935).

[0171] The protein sequence of CD320 derived from the above mRNA sequence is shown below: >sp|Q9NPF0|CD320_HUMAN CD320 Antigen OS=Homo sapiens OX=9606 GN=CD320 PE=1 SV=1

[0172] MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGPSSGSCPTKFQ

[0173] CRTSGLCVPLTWRCDRDLDCSDGSDEEEECRIEPCTQKGQCPPPPGLPPCCTGVSDCSGGT

[0174] DKKLRNCSRLACLAGELRCTLSDDCIPLTWRCDGHPDCPDSSDELGCGTNEILPEGDATT

[0175] MGPPVTLESVTSLRNATTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVLSA

[0176] SLVTATLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP(SEQ ID NO.936)

[0177] The CD320 mRNA sequence from Homo sapiens is shown below: >NM_001165895.2 Homo sapiens CD320 molecule (CD320), transcript variant 2, DNA

[0178]

[0179] The protein sequence from CD320 derived from the above mRNA sequence is shown below: >sp|Q9NPF0-2|CD320_HUMAN Isoform 2 of CD320 antigen OS=Homo sapiens OX=9606 GN=CD320

[0180] MSGGWMAQVGAWRTGALGLALLLLLGLGLGLEAAASPLSTPTSAQAAGIEPCTQKGQCPPPPGLPCPCTGVSDCSGGTDKKLRNCSRLACLAGELRCTLSDDCIPLTWRCDGHPDCPDSSDE LGCGTNEILPEGDATTMGPPVTLESVTSLRNATTMGPPVTLESVPSVGNATSSSAGDQSGSPTAYGVIAAAAVLSASLVTATLLLLSWLRAQERLRPLGLLVAMKESLLLSEQKTSLP(SEQ ID NO.938)

[0181] Additionally, as used herein, "LRP2" refers to a gene or protein. LRP2 is also known as megalin, LRP-2, glycoprotein 330, DBS, GP330, Gp330, calcium sensor protein, Heymann nephritis antigen homolog, low-density lipoprotein receptor-related protein 2, EC 1.1.2.3, EC 3.4.21.9, LDL receptor-related protein 2. The term LRP2 includes human LRP2, the amino acid and nucleotide sequences of which can be found, for example, at Genbank Accession No. NM_004525.3; mouse LRP2, the amino acid and nucleotide sequences of which can be found, for example, at Genbank Accession No. NM_001081088.2; and rat LRP2, the amino acid and nucleotide sequences of which can be found, for example, at Genbank Accession No. NM_030827.1. Additional examples of LRP2 mRNA sequences are readily available using, for example, GenBank. Additional information is found at Figure 18 .

[0182] An example of LRP2 is: >NM_004525.3 Homo sapiens LDL receptor-related protein 2 (LRP2), DNA:

[0183] GGTCTAAAGGGCTTTATGCACTGTCTGGAGGGTGGGGACTGGCGCGGGTAGAAAACGGGATGCCTCGGGC

[0184] GTGGGGGCAGGCTTTTGGCCACTAGGAGCTGGCGGAGGTGCAGACCTAAAGGAGCGTTCGCTAGCAGAGG

[0185] CGCTGCCGGTGCGGTGTGCTACGCGCGCCCACCTCCCGGGGAAGGAACGGCGAGGCCGGGGACCGTCGCG

[0186] GAGATGGATCGCGGGCCGGCAGCAGTGGCGTGCACGCTGCTCCTGGCTCTCGTCGCCTGCCTAGCGCCGG

[0187] CCAGTGGCCAAGAATGTGACAGTGCGCATTTTCGCTGTGGAAGTGGGCATTGCATCCCTGCAGACTGGAG

[0188] GTGTGATGGGACCAAAGACTGTTCAGATGACGCGGATGAAATTGGCTGCGCTGTTGTGACCTGCCAGCAG

[0189] GGCTATTTCAAGTGCCAGAGTGAGGGACAATGCATCCCCAACTCCTGGGTGTGTGACCAAGATCAAGACT

[0190] GTGATGATGGCTCAGATGAACGTCAAGATTGCTCACAAAGTACATGCTCAAGTCATCAGATAACATGCTC

[0191] CAATGGTCAGTGTATCCCAAGTGAATACAGGTGCGACCACGTCAGAGACTGCCCCGATGGAGCTGATGAG

[0192] AATGACTGCCAGTACCCAACATGTGAGCAGCTTACTTGTGACAATGGGGCCTGCTATAACACCAGTCAGA

[0193] AGTGTGATTGGAAAGTTGATTGCAGGGACTCCTCAGATGAAATCAACTGCACTGAGATATGCTTGCACAA

[0194] TGAGTTTTCATGTGGCAATGGAGAGTGTATCCCTCGTGCTTATGTCTGTGACCATGACAATGATTGCCAA

[0195] GACGGCAGTGACGAACATGCTTGCAACTATCCGACCTGCGGTGGTTACCAGTTCACTTGCCCCAGTGGCC

[0196] GATGCATTTATCAAAACTGGGTTTGTGATGGAGAAGATGACTGTAAAGATAATGGAGATGAAGATGGATG

[0197] TGAAAGCGGTCCTCATGATGTTCATAAATGTTCCCCAAGAGAATGGTCTTGCCCAGAGTCGGGACGATGC

[0198] ATCTCCATTTATAAAGTTTGTGATGGGATTTTAGATTGCCCAGGAAGAGAGATGAAAAACAACACTAGTA

[0199] CCGGAAAATACTGTAGTATGACTCTGTGCTCTGCCTTGAACTGCCAGTACCAGTGCCATGAGACGCCGTA

[0200] TGGAGGAGCGTGTTTTTGTCCCCAGGTTATATCATCAACCACAATGACAGCCGTACCTTGTGTTGAGTTT

[0201] GATGATTGCCAGATATGGGGAATTTGTGACCAGAAGTGTGAAAGCCGACCTGGCCGTCACCTGTGCCACT

[0202] GTGAAGAAGGGTATATCTTGGAGCGTGGACAGTATTGCAAAGCTAATGATTCCTTTGGCGAGGCCTCCAT

[0203] TATCTTCTCCAATGGTCGGGATTTGTTAATTGGTGATATTCATGGAAGGAGCTTCCGGATCCTAGTGGAG

[0204] TCTCAGAATCGTGGAGTGGCCGTGGGTGTGGCTTTCCACTATCACCTGCAAAGAGTTTTTTGGCAGACA

[0205] CCGTGCAAAATAAGGTTTTTTCAGTTGACATTAATGGTTTAAATATCCAAGAGGTTCTCAATGTTTCTGT

[0206] TGAACCCCAGAGAACCTGGCTGTGGACTGGGTTAATAATAAAATCTATCTAGTGGAAACCAAGGTCAAC

[0207] CGCATAGATATGGTAAATTTGGATGGAAGCTATCGGGTTACCCTTATAACTGAAAACTTGGGGCATCCTA

[0208] GAGGAATTGCCGTGGACCCAACTGTTGGTTATTTTATTTTTCTCAGATTGGGAGAGCCTTTCTGGGGAACC

[0209] TAAGCTGGAAAGGGCATTCATGGGATGGCAGCAACCGTAAAGACTTGGTGAAAAACAAAGCTGGGATGGCCT

[0210] GCTGGGGTAACTCTGGATATGATATCGAAGCGTGTTTTACTGGGTTGACTCTCGGTTTGATTACATTGAAA

[0211] CTGTAACTTATGATGGAATTCAAAGGAAGACTGTAGTTCATGGAGGCTCCCTCATTCCTCATCCCTTTGG

[0212] AGTAAGCTTATTTGAAGGTCAGGTGTTCTTACAGATTGGACAAAGATGGCCGTGCTGAAGGCAAACAAG

[0213] TTCACAGAGACCAACCCACAAGTGTACTACCAGGCTTCCCTGAGGCCCTATGGAGTGACTGTTTACCATT

[0214] CCCTCAGACAGCCCTATGCTACCAATCCGTGTAAAGATAACAATGGGGGCTGTGAGCAGGTCTGTGTCCT

[0215] CAGCCACAGAACAGATAATGATGGTTTGGGTTTCCGTTGCAAGTGCACATTCGGCTTCCAACTGGATACA

[0216] GATGAGCGCCACTGCATTGCTGTTCAGAATTTCCTCATTTTTTCATCCCAAGTTGCTATTCGTGGGATCC

[0217] CGTTCACCTTGTCTACCCAGGAAGATGTCATGGTTCCAGTTTCGGGGAATCCTTCTTTCTTTGTCGGGAT

[0218] TGATTTTGACGCCCAGGACAGCACTATCTTTTTTTCAGATATGTCAAAACACATGATTTTTAAGCAAAAG

[0219] ATTGATGGCACAGGAAGAGAAATTCTCGCAGCTAACAGGGTGGAAAATGTTGAAAGTTTGGCTTTTGATT

[0220] GGATTTCAAAGAATCTCTATTGGACAGACTCTCATTACAAGAGTATCAGTGTCATGAGGCTAGCTGATAA

[0221] AACGAGACGCACAGTAGTTCAGTATTTAAATAACCCACGGTCGGTGGTAGTTCATCCTTTTGCCGGGTAT

[0222] CTATTCTTCACTGATTGGTTCCGTCCTGCTAAAATTATGAGAGCATGGAGTGACGGATCTCACCTCTTGC

[0223] CTGTAATAAACACTACTCTTGGATGGCCCAATGGCTTGGCCATCGATTGGGCTGCTTCACGATTGTACTG

[0224] GGTAGATGCCTATTTTGATAAAATTGAGCACAGCACCTTTGATGGTTTAGACAGAAGAAGACTGGGCCAT

[0225] ATAGAGCAGATGACACATCCGTTTGGACTTGCCATCTTTGGAGAGCATTTATTTTTTACTGACTGGAGAC

[0226] TGGGTGCCATTATTCGAGTCAGGAAAGCAGATGGTGGAGAAATGACAGTTATCCGAAGTGGCATTGCTTA

[0227] CATACTGCATTTGAAATCGTATGATGTCAACATCCAGACTGGTTCTAACGCCTGTAATCAACCCACGCAT

[0228] CCTAACGGTGACTGCAGCCACTTCTGCTTCCCGGTGCCAAATTTCCAGCGAGTGTGTGGGTGCCCTTATG

[0229] GAATGAGGCTGGCTTCCAATCACTTGACATGCGAGGGGGACCCAACCAATGAACCACCCACAGAGCAGTG

[0230] TGGCTTATTTTCCTTCCCCTGTAAAAATGGCAGATGTGTGCCCAATTACTATCTCTGTGATGGAGTCGAT

[0231] GATTGTCATGATAACAGTGATGAGCAACTATGTGGCACACTTAATAATACCTGTTCATCTTCGGCGTTCA

[0232] CCTGTGGCCATGGGGAGTGCATTCCTGCACACTGGCGCTGTGACAAACGCAACGACTGTGTGGATGGCAG

[0233] TGATGAGCACAACTGCCCCACCCACGCACCTGCTTCCTGCCTTGACACCCAATACACCTGTGATAATCAC

[0234] CAGTGTATCTCAAAGAACTGGGTCTGTGACACAGACAATGATTGTGGGGATGGATCTGATGAAAAGAACT

[0235] GCAATTCGACAGAGACATGCCAACCTAGTCAGTTTAATTGCCCCAATCATCGATGTATTGACCTATCGTT

[0236] TGTCTGTGATGGTGACAAGGATTGTGTTGATGGATCTGATGAGGTTGGTTGTGTATTAAACTGTACTGCT

[0237] TCTCAATTCAAGTGTGCCAGTGGGGATAAATGTATTGGCGTCACAAATCGTTGTGATGGTGTTTTTGATT

[0238] GCAGTGACAACTCGGATGAAGCAGGCTGTCCAACCAGGCCTCCTGGTATGTGCCACTCAGATGAATTTCA

[0239] GTGCCAAGAAGATGGTATCTGCATCCCGAACTTCTGGGAATGTGATGGGCATCCAGACTGCCTCTATGGA

[0240] TCTGATGAGCACAATGCCTGTGTCCCCAAGACTTGCCCTTCATCATATTTCCACTGTGACAACGGAAACT

[0241] GCATCCACAGGGCATGGCTCTGTGATCGGGACAATGACTGCGGGGATATGAGTGATGAGAAGGACTGCCC

[0242] TACTCAGCCCTTTCGCTGTCCTAGTTGGCAATGGCAGTGTCTTGGCCATAACATCTGTGTGAATCTGAGT

[0243] GTAGTGTGTGATGGCATCTTTGACTGCCCCAATGGGACAGATGAGTCCCCACTTTGCAATGGGAACAGCT

[0244] GCTCAGATTTCAATGGTGGTTGTACTCACGAGTGTGTTCAAGAGCCCTTTGGGGCTAAATGCCTATGTCC

[0245] ATTGGGATTCTTACTTGCCAATGATTCTAAGACCTGTGAAGACATAGATGAATGTGATATTCTAGGCTCT

[0246] TGTAGCCAGCACTGTTACAATATGAGAGGTTCTTTCCGGTGCTCGTGTGATACAGGCTACATGTTAGAAA

[0247] GTGATGGGAGGACTTGCAAAGTTACAGCATCTGAGAGTCTGCTGTTACTTGTGGCAAGTCAGAACAAAAT

[0248] TATTGCCGACAGTGTCACCTCCCAGGTCCACAATATCTATTCATTGGTCGAGAATGGTTCTTACATTGTA

[0249] GCTGTTGATTTTGATTCAATTAGTGGTCGTATCTTTTGGTCTGATGCAACTCAGGGTAAAACCTGGAGTG

[0250] CGTTTCAAAATGGAACGGACAGAAGAGTGGTATTTGACAGTAGCATCATCTTGACTGAAACTATTGCAAT

[0251] AGATTGGGTAGGTCGTAATCTTTACTGGACAGACTATGCTCTGGAAACAATTGAAGTCTCCAAAATTGAT

[0252] GGGAGCCACAGGACTGTGCTGATTAGTAAAAACCTAACAAATCCAAGAGGACTAGCATTAGATCCCAGAA

[0253] TGAATGAGCATCTACTGTTCTGGTCTGACTGGGGCCACCACCCTCGCATCGAGCGAGCCAGCATGGACGG

[0254] CAGCATGCGCACTGTCATTGTCCAGGACAAGATCTTCTGGCCCTGCGGCTTAACTATTGACTACCCCAAC

[0255] AGACTGCTCTACTTCATGGACTCCTATCTTGATTACATGGACTTTTGTGATTATAATGGACACCATCGGA

[0256] GACAGGTGATAGCCAGTGATTTGATTATACGGCACCCCTATGCCCTAACTCTCTTTGAAGACTCTGTGTA

[0257] CTGGACTGACCGTGCTACTCGTCGGGTTATGCGAGCCAACAAGTGGCATGGAGGGAACCAGTCAGTTGTA

[0258] ATGTATAATATTCAATGGCCCCTTGGGATTGTTGCGGTTCATCCTTCGAAACAACCAAATTCCGTGAATC

[0259] CATGTGCCTTTTCCCGCTGCAGCCATCTCTGCCTGCTTTCCTCACAGGGGCCTCATTTTTACTCCTGTGT

[0260] TTGTCCTTCAGGATGGAGTCTGTCTCCTGATCTCCTGAATTGCTTGAGAGATGATCAACCTTTCTTAATA

[0261] ACTGTAAGGCAACATATAATTTTTGGAATCTCCCTTAATCCTGAGGTGAAGAGCAATGATGCTATGGTCC

[0262] CCATAGCAGGGATACAGAATGGTTTAGATGTTGAATTTGATGATGCTGAGCAATACATCTATTGGGTTGA

[0263] AAATCCAGGTGAAATTCACAGAGTGAAGACAGATGGCACCAACAGGACAGTATTTGCTTCTATATCTATG

[0264] GTGGGGCCTTCTATGAACCTGGCCTTAGATTGGATTTCAAGAAACCTTTATTCTACCAATCCTAGAACTC

[0265] AGTCAATCGAGGTTTTGACACTCCACGGAGATATCAGATACAGAAAAACATTGATTGCCAATGATGGGAC

[0266] AGCTCTTGGAGTTGGCTTTCCAATTGGCATAACTGTTGATCCTGCTCGTGGGAAGCTGTACTGGTCAGAC

[0267] CAAGGAACTGACAGTGGGGTTCCTGCCAAGATCGCCAGTGCTAACATGGATGGCACATCTGTGAAAACTC

[0268] TCTTTACTGGGAACCTCGAACACCTGGAGTGTGTCACTCTTGACATCGAAGAGCAGAAACTCTACTGGGC

[0269] AGTCACTGGAAGAGGAGTGATTGAAAAGGAAACGTGGATGGAAACAGATCGAATGATCCTGGTACACCAG

[0270] CTTTCCCACCCCTGGGGAATTGCAGTCCATGATTCTTTCCTTATTATACTGATGAAAGGTATGAGGTCA

[0271] TTGAAAGAGTTGATAAGGCCACTGGGGCCAACAAAATAGTCTTGAGAGATAATGTTCCAAATCTGAGGGG

[0272] TCTTCAAGTTTATCACAGACGCAATGCCGCCGAATCCTCAAATGGCTGTAGCAACAACATGAATGCCTGT

[0273] CAGCAGATTTGCCTGCCTGTACCAGGAGGATTGTTTTCCTGCGCCTGTGCCACTGGATTTAAACTCAATC

[0274] CTGATAATCGGTCCTGCTCTCCATATAACTCTTTCATTGTTGTTTCAATGCTGTCTGCAATCAGAGGCTT

[0275] TAGCTTGGAATTGTCAGATCATTCAGAAACCATGGTGCCGGTGGCAGGCCAAGGACGAAACGCACTGCAT

[0276] GTGGATGTGGATGTGTCCTCTGGCTTTATTTATTGGTGTGATTTTAGCAGCTCAGTGGCATCTGATAATG

[0277] CGATCCGTAGAATTAAACCAGATGGATCTTCTCTGATGAACATTGTGACACATGGAATAGGAGAAAATGG

[0278] AGTCCGGGGTATTGCAGTGGATTGGGTAGCAGGAAATCTTTATTTCACCAATGCCTTTGTTTCTGAAACA

[0279] CTGATAGAAGTTCTGCGGATCAATACTACTTACCGCCGTGTTCTTCTTAAAGTCACAGTGGACATGCCTA

[0280] GGCATATTGTTGTAGATCCCAAGAACAGATACCTCTTCTGGGCTGACTATGGGCAGAGACCAAAGATTGA

[0281] GCGTTCTTTCCTTGACTGTACCAATCGAACAGTGCTTGTGTCAGAGGGCATTGTCACACCACGGGGCTTG

[0282] GCAGTGGACCGAAGTGATGGCTACGTTTATTGGGTTGATGATTCTTTAGATATAATTGCAAGGATTCGTA

[0283] TCAATGGAGAGAACTCTGAAGTGATTCGTTATGGCAGTCGTTACCCAACTCCTTATGGCATCACTGTTTT

[0284] TGAAAATTCTATCATATGGGTAGATAGGAATTTGAAAAAGATCTTCCAAGCCAGCAAGGAACCAGAGAAC

[0285] ACAGAGCCACCCACAGTGATAAGAGACAATATCAACTGGCTAAGAGATGTGACCATCTTTGACAAGCAAG

[0286] TCCAGCCCCGGTCACCAGCAGAGGTCAACAACAACCCTTGCTTGGAAAACAATGGTGGGTGCTCTCCATCT

[0287] CTGCTTTGCTCTGCCTGGATTGCACACCCCAAAATGTGACTGTGCCTTTGGGACCCTGCAAAGTGATGGC

[0288] AAGAATTGTGCCATTTCAACAGAAAATTTCCTCATCTTTGCCTTGTCTAATTCCTTGAGAAGCTTACACT

[0289] TGGACCCTGAAAACCATAGCCCACCTTTCCAAACAATAAATGTGGAAAGAACTGTCATGTCTCTAGACTA

[0290] TGACAGTGTAAGTGATAGAATCTACTTCCACAAAATTTAGCCTCTGGAGTTGGACAGATTTCCTATGCC

[0291] ACCCTGTCTTCAGGGATCCATACTCCAACTGTCATTGCTTCAGGTATAGGGACTGCTGATGGCATTGCCT

[0292] TTGACTGGATTACTAGAAGAATTTATTACAGTGACTACCTCAACCAGATGATTAATTCCATGGCTGAAGA

[0293] TGGGTCTAACCGCACTGTGATAGCCCGCGTTCCAAAAACCAAGAGCAATTGTGTTAGATCCCTGCCAAGGG

[0294] TACCTGTACTGGGCTGACTGGGATACACATGCCAAAATCGAGAGAGCCACATTGGGAGGAAACTTCCGCG

[0295] TACCCATTGTGAACAGCAGTCTGGTCATGCCCAGTGGGCTGACTCTGGACTATGAAGAGGACCTTCTCTA

[0296] CTGGGTGGATGCTAGTCTGCAGAGGATTGAACGCAGCACTCTGACGGGCGTGGATCGTGAAGTCATTGTC

[0297] AATGCAGCCGTTCATGCTTTTGGCTTGACTCTCTATGGCCAGTATATTTACTGGACTGACTTGTACACAC

[0298] AAAGAATTTACCGAGCTAACAAATATGACGGGTCAGGTCAGATTGCAATGACCACAAATTTGCTCTCCCA

[0299] GCCCAGGGGAATCAACACTGTTGTGAAGAACCAGAAACAACAGTGTAACAATCCTTGTGAACAGTTTAAT

[0300] GGGGGCTGCAGCCATATCTGTGCACCAGGTCCAAATGGTGCCGAGTGCCAGTGTCCACATGAGGGCAACT

[0301] GGTATTTGGCCAACAACAGGAAGCACTGCATTGTGGACAATGGTGAACGATGTGGTGCATCTTCCTTCAC

[0302] CTGCTCCAATGGGCGCTGCATCTCGGAAGAGTGGAAGTGTGATAATGACAACGACTGTGGGGATGGCAGT

[0303] GATGAGATGGAAAGTGTCTGTGCACTTCACACCTGCTCACCGACAGCCTTCACCTGTGCCAATGGGCGAT

[0304] GTGTCCAATACTCTTACCGCTGTGATTACTACAATGACTGTGGTGATGGCAGTGATGAGGCAGGGTGCCT

[0305] GTTCAGGGACTGCAATGCCACCACGGAGTTTATGTGCAATAACAGAAGGTGCATACCTCGTGAGTTTATC

[0306] TGCAATGGTGTAGACAACTGCCATGATAATAACACTTCAGATGAGAAAAATTGCCCTGATCGCACTTGCC

[0307] AGTCTGGATACACAAAATGTCATAATTCAAATATTTGTATTCCTCGCGTTTATTTGTGTGACGGAGACAA

[0308] TGACTGTGGAGATAACAGTGATGAAAACCCTACTTATTGCACCACTCACACGTGCAGCAGCAGTGAGTTC

[0309] CAATGCGCATCTGGGCGCTGTATTCCTCAACATTGGTATTGTGATCAAGAAACAGATTGTTTTGATGCCT

[0310] CTGATGAACCTGCCTCTTGTGGTCACTCTGAGCGAACATGCCTAGCTGATGAGTTCAAGTGTGATGGTGG

[0311] GAGGTGCATCCCAAGCGAATGGATCTGTGACGGTGATAATGACTGTGGGGATATGAGTGACGAGGATAAA

[0312] AGGCACCAGTGTCAGAATCAAAACTGCTCGGATTCCGAGTTTCTCTGTGTAAATGACAGACCTCCGGACA

[0313] GGAGGTGCATTCCCCAGTCTTGGGTCTGTGATGGCGATGTGGATTGTACTGACGGCTACGATGAGAATCA

[0314] GAATTGCACCAGGAGAACTTGCTCTGAAAATGAATTCACCTGTGGTTACGGACTGTGTATCCCAAAGATA

[0315] TTCAGGTGTGACCGGCACAATGACTGTGGTGACTATAGCGACGAGAGGGGCTGCTTATACCAGACTTGCC

[0316] AACAGAATCAGTTTACCTGTCAGAACGGGCGCTGCATTAGTAAAACCTTCGTCTGTGATGAGGATAATGA

[0317] CTGTGGAGACGGATCTGATGAGCTGATGCACCTGTGCCACACCCCAGAACCCACGTGTCCACCTCACGAG

[0318] TTCAAGTGTGACAATGGGCGCTGCATCGAGATGATGAAACTCTGCAACCACCTAGATGACTGTTTGGACA

[0319] ACAGCGATGAGAAAGGCTGTGGCATTAATGAATGCCATGACCCTTCAATCAGTGGCTGCGATCACAACTG

[0320] CACAGACACCTTAACCAGTTTCTATTGTTCCTGTCGTCCTGGTTACAAGCTCATGTCTGACAAGCGGACT

[0321] TGTGTTGATATTGATGAATGCACAGAGATGCCTTTTGTCTGTAGCCAGAAGTGTGAGAATGTAATAGGCT

[0322] CCTACATCTGTAAGTGTGCCCCAGGCTACCTCCGAGAACCAGATGGAAAGACCTGCCGGCAAAACAGTAA

[0323] CATCGAACCCTATCTCATTTTTAGCAACCGTTACTATTTGAGAAATTTAACTATAGATGGCTATTTTTAC

[0324] TCCCTCATCTTGGAAGGACTGGACAATGTTGTGGCATTAGATTTTGACCGAGTAGAGAAGAGATTGTATT

[0325] GGATTGATACACAGAGGCAAGTCATTGAGAGAATGTTTCTGAATAAGACAAACAAGGAGACAATCATAAA

[0326] CCACAGACTACCAGCTGCAGAAAGTCTGGCTGTAGACTGGGTTTCCAGAAAGCTCTACTGGTTGGATGCC

[0327] CGCCTGGATGGCCTCTTTGTCTCTGACCTCAATGGTGGACACCGCCGCATGCTGGCCCAGCACTGTGTGG

[0328] ATGCCAACAACACCTTCTGCTTTGATAATCCCAGAGGACTTGCCCTTCACCCTCAATATGGGTACCTCTA

[0329] CTGGGCAGACTGGGGTCACCGCGCATACATTGGGAGAGTAGGCATGGATGGAACCAACAAGTCTGTGATA

[0330] ATCTCCACCAAGTTAGAGTGGCCTAATGGCATCACCATTGATTACACCAATGATCTACTCTACTGGGCAG

[0331] ATGCCCACCTGGGTTACATAGAGTACTCTGATTTGGAGGGCCACCATCGACACACGGTGTATGATGGGGC

[0332] ACTGCCTCACCCTTTCGCTATTACCATTTTTGAAGACACTATTTATTGGACAGATTGGAATACAAGGACA

[0333] GTGGAAAAGGGAAACAAATATGATGGATCAAATAGACAGACACTGGTGAACACAACACACAGACCATTTG

[0334] ACATCCATGTGTACCATCCATATAGGCAGCCCATTGTGAGCAATCCCTGTGGTACCAACAATGGTGGCTG

[0335] TTCTCATCTCTGCCTCATCAAGCCAGGAGGAAAAGGGTTCACTTGCGAGTGTCCAGATGACTTCCGCACC

[0336] CTTCAGCTGAGTGGCAGCACCTACTGCATGCCCATGTGCTCCAGCACCCAGTTCCTGTGCGCTAACAATG

[0337] AAAAGTGCATTCCTATCTGGTGGAAATGTGATGGACAGAAAGACTGCTCAGATGGCTCTGATGAACTGGC

[0338] CCTTTGCCCGCAGCGCTTCTGCCGACTGGGACAGTTCCAGTGCAGTGACGGCAACTGCACCAGCCCGCAG

[0339] ACTTTATGCAATGCTCACCAAAATTGCCCTGATGGGTCTGATGAAGACCGTCTTCTTTGTGAGAATCACC

[0340] ACTGTGACTCCAATGAATGGCAGTGCGCCAACAAACGTTGCATCCCAGAATCCTGGCAGTGTGACACATT

[0341] TAACGACTGTGAGGATAACTCAGATGAAGACAGTTCCCACTGTGCCAGCAGGACCTGCCGGCCGGGCCAG

[0342] TTTCGGTGTGCTAATGGCCGCTGCATCCCGCAGGCCTGGAAGTGTGATGTGGATAATGATTGTGGAGACC

[0343] ACTCGGATGAGCCCATTGAAGAATGCATGAGCTCTGCCCATCTCTGTGACAACTTCACAGAATTCAGCTG

[0344] CAAAACAAATTACCGCTGCATCCCAAAGTGGGCCGTGTGCAATGGTGTAGATGACTGCAGGGACAACAGT

[0345] GATGAGCAAGGCTGTGAGGAGAGGACATGCCATCCTGTGGGGGATTTCCGCTGTAAAAATCACCACTGCA

[0346] TCCCTCTTCGTTGGCAGTGTGATGGGCAAAATGACTGTGGAGATAACTCAGATGAGGAAAACTGTGCTCC

[0347] CCGGGAGTGCACAGAGAGCGAGTTTCGATGTGTCAATCAGCAGTGCATTCCCTCGCGATGGATCTGTGAC

[0348] CATTACAACGACTGTGGGGACAACTCAGATGAACGGGACTGTGAGATGAGGACCTGCCATCCTGAATATT

[0349] TTCAGTGTACAAGTGGACATTGTGTACACAGTGAACTGAAATGCGATGGATCCGCTGACTGTTTGGATGC

[0350] GTCTGATGAAGCTGATTGTCCCACACGCTTTCCTGATGGTGCATACTGCCAGGCTACTATGTTCGAATGC

[0351] AAAAACCATGTTTGTATCCCGCCATATTGGAAATGTGATGGCGATGATGACTGTGGCGATGGTTCAGATG

[0352] AAGAACTTCACCTGTGCTTGGATGTTCCCTGTAATTCACCAAACCGTTTCCGGTGTGACAACAATCGCTG

[0353] CATTTATAGTCATGAGGTGTGCAATGGTGTGGATGACTGTGGAGATGGAACTGATGAGACAGAGGAGCAC

[0354] TGTAGAAAACCGACCCCTAAACCTTGTACAGAATATGAATATAAGTGTGGCAATGGGCATTGCATTCCAC

[0355] ATGACAATGTGTGTGATGCCGATGACTGTGGTGACTGGTCCGATGAACTGGGTTGCAATAAAGGAAA

[0356] AGAAAGAACATGTGCTGAAAATATATGCGAGCAAAATTGTACCCAATTAAATGAAGGAGGATTTATCTGC

[0357] TCCTGTACAGCTGGGTTCGAAACCAATGTTTTTGACAGAACCTCCTGTCTAGATATCAATGAATGTGAAC

[0358] AATTTGGGACTTGTCCCCAGCACTGCAGAAATACCAAAGGAAGTTATGAGTGTGTTCTGTGCTGATGGCTT

[0359] CACGTCTATGAGTGACCGCCCTGGAAAACGATGTGCAGCTGAGGGTAGCTCTCCTTTGTTGCTACTGCCT

[0360] GACAATGTCCGAATTCGAAAATATAATCTCTCATCTGAGAGGTTCTCAGAGTATCTTCAAGATGAGGAAT

[0361] ATATCCAAGCTGTTGATTATGATTGGGATCCCAAGGACATAGGCCTCAGTGTTGTGTATTACACTGTGCG

[0362] AGGGGAGGGCTCTAGGTTTGGTGCTATCAAACGTGCCTACATCCCCAACTTTGAATCCGGCCGCAATAAT

[0363] CTTGTGCAGGAAGTTGACCTGAAACTGAAATACGTAATGCAGCCAGATGGAATAGCAGTGGACTGGGTTG

[0364] GAAGGCATATTTACTGGTCAGATGTCAAGAATAAACGCATTGAGGTGGCTAAACTTGATGGAAGGTACAG

[0365] AAAGTGGCTGATTTCCACTGACCTGGACCAACCAGCTGCTATTGCTGTGAATCCCAAACTAGGGCTTATG

[0366] TTCTGGACTGACTGGGGAAAGGAACCTAAAATCGAGTCTGCCTGGATGAATGGAGAGGACCGCAACATCC

[0367] TGGTTTTCGAGGACCTTGGTTGGCCAACTGGCCTTTCTATCGATTATTTGAACAATGACCGAATCTACTG

[0368] GAGTGACTTCAAGGAGGACGTTATTGAAACCATAAAATATGATGGGACTGATAGGAGAGTCATTGCAAAG

[0369] GAAGCAATGAACCCTTACAGCCTGGACATCTTTGAAGACCAGTTATACTGGATATCTAAGGAAAAGGGAG

[0370] AAGTATGGAAACAAAATAAATTTGGGCAAGGAAAGAAAGAGAAAACGCTGGTAGTGAACCCTTGGCTCAC

[0371] TCAAGTTCGAATCTTTCATCAACTCAGATACAATAAGTCAGTGCCCAACCTTTGCAAACAGATCTGCAGC

[0372] CACCTCTGCCTTCTGAGACCTGGAGGATACAGCTGTGCCTGTCCCCAAGGCTCCAGCTTTATAGAGGGGA

[0373] GCACCACTGAGTGTGATGCAGCCATCGAACTGCCTATCAACCTGCCCCCCCCATGCAGGTGCATGCACGG

[0374] AGGAAATTGCTATTTTGATGAGACTGACCTCCCCAAATGCAAGTGTCCTAGCGGCTACACCGGAAAATAT

[0375] TGTGAAATGGCGTTTTCAAAAGGCATCTCTCCAGGAACAACCGCAGTAGCTGTGCTGTTGACAATCCTCT

[0376] TGATCGTCGTAATTGGAGCTCTGGCAATTGCAGGATTCTTCCACTATAGAAGGACCGGCTCCCTTTTGCC

[0377] TGCTCTGCCCAAGCTGCCAAGCTTAAGCAGTCTCGTCAAGCCCTCTGAAAATGGGAATGGGGTGACCTTC

[0378] AGATCAGGGGCAGATCTTAACATGGATATTGGAGTGTCTGGTTTTGGACCTGAGACTGCTATTGACAGGT

[0379] CAATGGCAATGAGTGAAGACTTTGTCATGGAAATGGGGAAGCAGCCCATATAATTTGAAAACCCAATGTA

[0380] CTCAGCCAGAGACAGTGCTGTCAAAGTGGTTCAGCCAATCCAGGTGACTGTATCTGAAAATGTGGATAAT

[0381] AAGAATTATGGAAGTCCCATAAACCCTTCTGAGATAGTTCCAGAGAACAAACCCAACTTCACCAGCTGCTG

[0382] ATGGAACTCAGGTGACAAAAATGGAATCTCTTCAAACGAAAATCTAAAACAAACTACCACTTTGAAAATCC

[0383] AATCTATGCACAGATGGAGAACGAGCAAAAGGAAAGTGTTGCTGCGACACCACCTCCATCACCTTCGCTC

[0384] CCTGCTAAGCCTAAGCCTCCTTCGAGAAGAGACCCAACTCCAACCTATTCTGCAACAGAAGACACTTTTA

[0385] AAGACACCGCAAATCTTGTTAAAGAAGACTCTGAAGTATAGCTATACCAGCTATTTAGGGAATAATTAGA

[0386] AACACACTTTTGCACATATATTTTTTACAAACAGATGAAAAAAGTTAACATTCAGTACTTTATGAAAAAA

[0387] ATATATTTTTCCCTGTTTGCCTATAGTTGGAGGTATCCTGTGTGTCTTTTTTTACTTATGCCGTCTCATA

[0388] TTTTTACAAATAATTATCACAATGTACTATATGTATATCTTTGCACTGAAGTTGTCTGAAGGTAATACTA

[0389] TAAATATATTGTATATTTGTAAATTTTGGAAAGATTATCCTGTTACTGAATTTGCTAATAAAGATGTCTG

[0390] CTGATTTGGTTGGTGATCATTATAGTAAATGATCCAACAAGAAAAGGAATTGACTGGGGACCTTTAGCCG

[0391] TGTCTAAAGAAGAGGCACCACTCATATTTCCTATAAAATTATCTAGGAAAGGAATCCAGGCCCCGCTCTT

[0392] GGGTCCATTTTTACACATTAGCACTTAATTAATGTTCAATATTACATGTCAATTTGATTAATGGCTATGT

[0393] TGATAGGGGCCACTATGTGTTGTATAGACATCTGGACTTGACTGTAGACTCCTCAGATAATACAGAAGGT

[0394] AGGAAAAGCAATTCAGTTTGGCCCTTCTGTGTGTTGGCATTGTCTAACCAGAACTCTCTGTTTCATGTGT

[0395] GTTCTCTCACTAGCTGCCAAGACAACATTTTTATTTGTGATGTCTATGAGGAAATCCCATATCATTAAGT

[0396] GCCAGTGTCCTGCATTGAGTTTGTGGTTAATTAAATGAGCTCTTCTGCTGATGGACCCTGGAGCAATTTC

[0397] TCCCCTCACCTGACATTCAAGGTGGTCACCTGCCCTAGTAGTTGGAGCTCAGTAGCTGAATTTCTGAAAC

[0398] CAAATCTGTGTCTTCATAAAATAAGGTGCAAAAAAAAAAAAATACCAGTTAAGTAAAGCCTCAACTGGGTT

[0399] TTTGTTTCTATGAAAATATCATTATAATCACTATTTATTTCCTAAGTTGAACCTGAATAGAAAGGGAAAC

[0400] CATTCTTATTAAGCTTTTTATTAGGCCCTGTGGCTAAATGTGTACATTTATATTAGAATGTACTGTACAG

[0401] TCCAGATTCTTTTCTTTAATTCTTATTGGTTTTTTTTTTTTTTTTTTTTTTTTAGAGATGGAGTCTTGCTATA

[0402] TTGCCAAGGCTGATCTTGAAGTCCTGGGCTCAAGTGATCCTCCCACCTCAGCCTCCTGAGTGGTTGGGGT

[0403] TACGGGCGTGAGCCACTGTGCCTGGCTTCCAGCTCTCTCTCTTAAATAGTGGGTATAGTCTGCACAACAGG

[0404] AACCATGGCAGGAATATACACTTTCCCATAGCAAATAGCATACCTGACTCTCTGTGCTAATATTGCACAT

[0405] TTGTTAAACAATGAATGAATGGATGGATGGATGGATGGATGAATGAATGAAACATATACTACTGATTATT

[0406] TTATTCCAGAGTTCTCAAAATATTTGTTGCTGATATTTTGAGTGCTGACTGTAATTACTTTGATTAGATA

[0407] AACAACTGGAAATAATGCTGCTGAAAAAGTTCTAATAAATGTGTATTTTATCAGA (SEQ ID NO. 939).

[0408] An example of a protein sequence from the above LRP2 mRNA is: >sp|P98164|LRP2_human low-density lipoprotein receptor-related protein 2 OS=Homo sapiens OX=9606 GN=LRP2 PE=1 SV=3

[0409] MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEI

[0410] GCAVVTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSDERQDCSQSTCSSHQITCSNGQC

[0411] IPSEYRCDHVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCT

[0412] EICLHNEFSCGNGGECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWV

[0413] CDGEDDCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENN

[0414] TSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDSRTCVEFDDCQIWGICDQ

[0415] KCESRPGRHLCHCEEGYILERGQYCKANDSFGEASIIFSNGRDLLIGDIHGRSFRILVES

[0416] QNRGVAVGVAFHYHLQRVFWTDTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNK

[0417] IYLVETKVNRIDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLER

[0418] AFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDGIQRKTVVHGGSL

[0419] IPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQASLRPYGVTVYHSLRQPYAT

[0420] NPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIR

[0421] GIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAA

[0422] NRVENVESLAFDWISKNLYWTDSHYKISSVMRLADKTRRTVVQYLNNPRSVVVHPFAGYL

[0423] FFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEHSTFD

[0424] GLDRRRLGHIEQMTHPFGLAIFGEHLFFTDWRLGAIIRWRKADGGEMTVIRSGIAYILHL

[0425] KSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNE

[0426] PPTEQCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNTCSSSAFTCGHGECI

[0427] PAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDE

[0428] KNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKC

[0429] IGVTNRCDGVFDCSDNSDEAGCPTRPPGMCHSDEFQCQEDGICPNFWECDGHPDCLYGS

[0430] DEHNACVPKTCPSSYFHCDNGNCIHRAWLCDRNDCGDMSDEKDCPTQPFRCPSWQWQCL

[0431] GHNICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFL

[0432] LANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYMLESDGRTCKVTASESLLLLV

[0433] ASQNKIIADSVTSQVHNIYSLVENGSYIVAVDFDSISGRIFWSDATQGKTWSAFQNGTDR

[0434] RVVFDSSIILTETIAIDWVGRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALD

[0435] PRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDSYLD

[0436] YMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRRVMRANKWHGGNQSVVM

[0437] YNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCPSGWSLSPDLLNC

[0438] LRDDQPFLITVRQHIIFGISLNPEVKSNDAMVPIAGIQNGLDVEFDDAEQYIYWVENPGE

[0439] IHRVKTDGTNRTVFASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRYRKTL

[0440] IANDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVKTLFTGNLEH

[0441] LECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQLSHPWGIAVHDSFLYYTDEQY

[0442] EVIERVDKATGANKIVLRDNVPNLRGLQVYHRRNAAESSNGCSNNMNACQQICLPVPGGL

[0443] FSCACATGFKLNPDNRSCSPYNSFIVVSMLSAIRGFSLELSDHSETMVPVAGQGRNALHV

[0444] DVDVSSGFIYWCDFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVAGNLY

[0445] FTNAFVSETLIEVLRINTTYRRVLLKVTVDMPRHIVVDPKNRYLFWADYGQRPKIERSFL

[0446] DCTNRTVLVSEGIVTPRGLAVDRSDGYVYWVDDSLDIIARIRINGENSEVIRYGSRYPTP

[0447] YGITVFENSIIWVDRNLKKIFQASKEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAE

[0448] VNNNPCLENNGGCSHLCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRS

[0449] LHLDPENHSPPFQTINVERTVMSLDYDSVSDRIYFTQNLASGVGQISYATLSSGIHTPTV

[0450] IASGIGTADGIAFDWITRRIYYSDYLNQMINSMAEDGSNRTVIARVPKPRAIVLDPCQGY

[0451] LYWADWDTHAKIERATLGGNFRVPIVNSSLVMPSGLTLDYEEDLLYWVDASLQRIERSTL

[0452] TGVDREVIVNAAVHAFGLTLYGQYIYWTDLYTQRIYRANKYDGSGQIAMTTNLLSQPRGI

[0453] NTVVKNQKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANNRKHCIVDNGERC

[0454] GASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPTAFTCANGRCVQYSYRC

[0455] DYYNDCGDGSDEAGCLFRDCNATTEFMCNNRRCIPREFICNGVDNCHDNNTSDEKNCPDR

[0456] TCQSGYTKCHNSNICIPRVYLCDGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQH

[0457] WYCDQETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKR

[0458] HQCQNQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCTRRTCSENEFTC

[0459] GYGLCIPKIFRCDRHNDCGDYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDG

[0460] SDELMHLCHTPEPTCPPHEFKCDNGRCIEMMKLCNHLDDCLDNSDEKGCGINECHDPSIS

[0461] GCDHNCTDTLTSFYCSCRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAP

[0462] GYLREPDGKTCRQNSNIEPYLIFSNRYYLRNLTIDGYFYSLILEGLDNVVALDFDRVEKR

[0463] LYWIDTQRQVIERMFLNKTNKETIINHRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLN

[0464] GGHRRMLAQHCVDANNTFCFDNPRGLALHPQYGYLYWADWGHRAYIGRVGMDGTNKSVII

[0465] STKLEWPNGITIDYTNDLLYWADAHLGYIEYSDLEGHHRHTVYDGALPHPFAITIFEDTI

[0466] YWTDWNTRTVEKGNKYDGSNRQTLVNTTHRPFDIHVYHPYRQPIVSNPCGTNNGGCSHLC

[0467] LIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCANNEKCIPIWWKCDGQKDCSD

[0468] GSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQNCPDGSDEDRLLCENHHCDSNEWQ

[0469] CANKRCIPESWQCDTFNDCEDNSDEDSSHCASRTCRPGQFRCANGRCIPQAWKCDVDNDC

[0470] GDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCH

[0471] PVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRWICDH

[0472] YNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGA

[0473] YCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCIYSH

[0474] EVCNGVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDEL

[0475] GCNKGKERTCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCPQH

[0476] CRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQD

[0477] EEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIKRAYIPNFESGRNNLVQEVDLKLKY

[0478] VMQPDGIAVDWVGRHIYWSDVKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMF

[0479] WTDWGKEPKIESAWMNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYD

[0480] GTDRRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKQNKFGQGKKEKTLVVNPWLTQVRI

[0481] FHQLRYNKSVPNLCKQICSHLLCLRPGGYSCACPQGSSFIEGSTTECDAAIELPINLPPP

[0482] CRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSKGISPGTTAVAVLLTILLIVVIGAL

[0483] AIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAI

[0484] DRSMAMSEDFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVTVSENVDNKNYGSPINPSE

[0485] IVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQKESVAATPPPSPSLP

[0486] AKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV(SEQ ID NO.940).

[0487] As used herein, "target sequence" refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during transcription of a gene of interest, eg, CD320 gene or LRP2 gene, including mRNA that is an RNA processing product of the primary transcription product.

[0488] As used herein, the term "strand comprising a sequence" refers to an oligonucleotide comprising a chain of nucleotides described by referring to the sequence using standard nucleotide nomenclature.

[0489] "G", "C", "A" and "U" generally represent nucleotides containing guanine, cytosine, adenine and uracil as bases, respectively. "T" and "dT" are used interchangeably herein and represent deoxyribonucleotides in which the nucleobase is thymine, e.g., deoxyribothymine, 2'-deoxythymidine or thymidine. However, it will be understood that the terms "ribonucleotide" or "nucleotide" or "deoxyribonucleotide" may also refer to modified nucleotides (as described in further detail below) or alternative replacement moieties. It will be appreciated by those skilled in the art that guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide (including nucleotides having such replacement moieties). For example, without limitation, a nucleotide comprising inosine as its base may base pair with a nucleotide containing adenine, cytosine, or uracil. Thus, nucleotides containing uracil, guanine, or adenine may be replaced in the nucleotide sequences of the present invention by nucleotides containing, for example, inosine. Sequences comprising these replacement moieties are embodiments of the present invention.

[0490] The term "siRNA" refers to a compound, mixture, composition or reagent containing RNA as defined herein and mediating targeted cleavage of RNA transcripts by the RISC / AGO (RNA-induced silencing complex) complex, whereby the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC / AGO complex having RNase cleavage activity, thereby causing mRNA degradation, and the protein encoded by the mRNA is not produced or is produced at a reduced level compared to untreated cells. This results in a "knockdown" effect or reduced protein level of the gene targeted by the siRNA compared to control treated cells. The siRNA regulates, for example, inhibits the expression of CD320 or LRP2 in a cell, for example, a cell within a subject, such as a mammalian subject.

[0491] In one embodiment, the RNAi reagent of the present invention includes a single-stranded RNA that interacts with a target RNA sequence, for example, a CD320 or LRP2 target mRNA sequence to guide the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double-stranded RNA introduced into cells is broken down into siRNA by a type III nuclease called Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer (ribonuclease-III-like enzyme) processes dsRNA into short interfering RNAs of 19-23 base pairs (bp) with characteristic two-base 3' overhangs (Bernstein, et al., (2001) Nature 409:363). Initially, siRNA can be composed of two RNA strands, an antisense (or guide) strand and a sense (or passenger) strand, which form a double helix with or without a 3' nucleotide overhang varying in length from 10-80 bp. dsRNA can include one or more single-stranded overhangs of one or more nucleotides. In one embodiment, at least one end of the dsRNA has a single-stranded nucleotide overhang of 1 to 4, typically 1 or 2 nucleotides. In another embodiment, the antisense strand of the dsRNA has a 1-10 nucleotide overhang, which is located at the 3' end and the 5' end of the sense strand, respectively. In other embodiments, the sense strand of the dsRNA has a 1-10 nucleotide overhang, which is located at the 3' end and the 5' end of the antisense strand, respectively.

[0492] The siRNA is then incorporated into the RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA double helix, enabling the complementary antisense (guide) strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Once bound to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect, the present invention relates to single-stranded RNA (siRNA) that is produced within a cell and promotes RISC complex formation to achieve silencing of a target gene, i.e., CD320 or LRP2 gene. Therefore, the term "siRNA" is also used herein to refer to RNAi as described above.

[0493] In another embodiment, the RNAi agent can be a single-stranded siRNA introduced into a cell or organism to inhibit a target mRNA. The single-stranded RNAi agent binds to the RISC endonuclease Argonaute 2, which then cleaves the target mRNA. Single-stranded siRNAs are typically 15-80 nucleotides and can be chemically modified to improve metabolic stability and activity; wherein one or more pyrimidine nucleotides can be modified to 2'-deoxy-2'-fluoro nucleotides, one or more purine nucleotides can be modified to 2'-deoxy purine nucleotides, and further, wherein the terminal cap modification can be present at the 3' or 5' end; specifically by introducing one or more 2'-deoxythymidine nucleotides or by introducing one or more phosphorothioate groups to any nucleotide in the linker sequence, but particularly any nucleotide at the 3' or 5' end. In addition, a 3'-terminal phosphate or vinylphosphonate group can be introduced. Examples of such modifications would include, but are not limited to, modifications to the ribose portion of the nucleotide such as 2'-deoxy, 2'-deoxyfluoro, 2'-methoxy (2'-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2'-methoxyethyl, where it is understood that the stereochemistry of the 2'-substituent may be in either ribose- or arabinose-orientation. Another modification may be 2'-trifluoromethoxy. Other modifications to the ribose moiety can include bridging modifications, whereby the 2'-carbon of the sugar moiety is covalently linked to the 4'-carbon of the sugar moiety by a methylene or methoxymethylene group to provide nucleotides (Corey et al., (2018) Nuc Acid Res 46; 1584-1600) that are bridged in the art as LNA and (S)-cET, respectively. Additionally, the sugar moiety can be modified by removing the bond between carbon C2' and C3' to provide "open" chain nucleotides similar to those in WO2011 / 139843 A2. The ribose moiety of RNA nucleotides can also be replaced by a morpholino group to provide a PMO nucleotide. Modification of the phosphodiester moiety of the nucleotide is also possible and can include, but is not limited to, replacement of the phosphodiester group by phosphorothioate and phosphorothioamidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the strands can be modified with 2'-deoxynucleotides such as dT, and in addition, dT nucleotides can be modified by phosphorothioate groups instead of diphosphates.The design and testing of single-stranded siRNAs are described in U.S. Patent No. 8,101,348 and Lima et al., (2012) Cell 150:883-894, the entire contents of which are hereby incorporated by reference herein. Any antisense nucleotide sequence described herein can be used as a single-stranded siRNA chemically modified as described herein or as described by the methods described in Lima et al., (2012) Cell 150; 883-894.

[0494] In another embodiment, the "RNAi" used in the compositions, uses and methods of the present invention is double-stranded RNA and is referred to herein as a "double-stranded RNAi agent," "double-stranded RNA (dsRNA) molecule," "dsRNA agent," or "dsRNA." The term "dsRNA" refers to a complex of ribonucleic acid molecules having a double helical structure comprising two antiparallel and substantially complementary nucleic acid strands, which are referred to as having "sense" (passenger) and "antisense" (guide) orientations relative to the target RNA, i.e., the CD320 gene or the LRP2 gene. In some embodiments of the present invention, the double-stranded RNA (dsRNA) triggers the degradation of the target RNA, e.g., mRNA, by a post-transcriptional gene silencing mechanism referred to herein as RNA interference or RNAi.

[0495] Typically, most of the nucleotides of each chain of the dsRNA molecule are ribonucleotides, but as described in detail herein, any one or both of the two chains can also include one or more non-ribonucleotides, for example, deoxyribonucleotides and / or modified nucleotides. In addition, as used in this specification, "RNAi reagents" can include chemically modified ribonucleotides (Corey et al., (2018) Nuc Acid Res 46; 1584-1600); RNAi reagents can include significant modifications of multiple nucleotides or in single nucleotides. These modifications can include all types of modifications disclosed herein or known in the art. For the purposes of this specification and claims, "RNAi reagents" encompass any of these modifications as used in siRNA type molecules. Examples of such modifications would include, but are not limited to, modifications to the ribose portion of the nucleotide such as 2'-deoxy, 2'-deoxyfluoro, 2'-methoxy (2'-O-methyl) (Hutvanger et al., (2004) PLOS Biol 2, 0465-0475; Janas et al., (2019) Nuc Acid Res 47, 3306-3320; Jackson et al., (2006) RNA 12, 1197-1205), and 2'-methoxyethyl, where it is understood that the stereochemistry of the 2'-substituent can be in either ribose- or arabinose-orientation. Another modification can be 2'-trifluoromethoxy. Other modifications to the ribose moiety can include bridging modifications, whereby the 2'-carbon of the sugar moiety is covalently linked to the 4'-carbon of the sugar moiety via a methylene or methoxymethylene group to provide nucleotides that are bridged in the art as LNA and (S)-cET, respectively (Corey et al., (2018) NucAcid Res 46; 1584-1600). Additionally, the sugar moiety can be modified by removing the bond between carbon C2' and C3' to provide "open" chain nucleotides similar to those in WO 2011 / 139843 A2. The ribose moiety of RNA nucleotides can also be replaced by a morpholino group to provide a PMO nucleotide. Modification of the phosphodiester moiety of the nucleotide is also possible and can include, but is not limited to, replacement of the phosphodiester group by phosphorothioate and phosphorothioamidate (Eckstein et al., (2014) Nuc Acid Therapeutics 24, 374-387). The ends of the sense and antisense strands can be modified with 2'-deoxynucleotides, such as dT, and in addition, the dT nucleotides can be modified by phosphorothioate groups instead of diphosphates (Figure 19).

[0496] The ribonucleotides can be chemically modified at any single nucleotide or combination of nucleotides in the antisense and sense strands. In some cases, all nucleotides in either the antisense or sense strand, or in both the antisense and sense strands, are chemically modified (Allerson et al., (2005) J Med Chem 48, 901-904). In other cases, only some nucleotides in either the antisense or sense strand, or in both the antisense and sense strands, are chemically modified (Chiu et al., (2003) RNA 9, 1034-1048). In other cases, the modifications may follow a pattern of alternating 2'-methoxy and 2'-fluoro modifications on either or both strands of the siRNA and sometimes the complementary nucleotides of the antisense and sense strands may contain different chemical modifications, for example, where one member of the complementary nucleotide pair has a 2'-methoxy modification and the other member has a 2'-fluoro modification (Choung et al. (2006) Biochem Biophys Res Commun 342, 919-927; Hassler et al., (2018) Nucleic Acid Res 46, 2185-2196).

[0497] The two chains forming a double helix structure can be different parts of a larger RNA molecule, or they can be independent RNA molecules. When these two chains are parts of a larger molecule, and therefore connected by the uninterrupted nucleotide chain between the 5'-end of the other chain separately forming the double helix structure, the RNA chain connected is referred to as a "hairpin loop". When these two chains are covalently linked by a mode other than the uninterrupted nucleotide chain between the 3'-end of a chain and the 5'-end of the other chain separately forming the double helix structure, the structure connected is referred to as a "joint". These RNA chains can have the same or different numbers of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest chain of the dsRNA minus any overhangs present in the double helix. Except for the double helix structure, the RNAi reagent can comprise one or more nucleotide overhangs.

[0498] In one embodiment, the RNAi agent of the invention is a 20-30 nucleotide dsRNA that interacts with a target RNA sequence, eg, a CD320 target mRNA sequence or an LRP2 target mRNA sequence, to direct cleavage of the target RNA.

[0499] The term "antisense strand" refers to the strand of a double-stranded RNAi agent that includes a region that is substantially complementary to a target sequence (e.g., human CD320 mRNA or LRP2 mRNA). As used herein, the term "region complementary to a portion of an mRNA encoding CD320 or LRP2" refers to a region on the antisense strand that is substantially complementary to a portion of an mRNA sequence encoding either CD320 or LRP2. Where the region of complementarity is not fully complementary to the target sequence, mismatches are most tolerated in the terminal regions, and if present, they are typically within 6, 5, 4, 3, or 2 nucleotides of the 5' and / or 3' ends. For example, in certain embodiments, substantially complementary can mean that in a hybridizing nucleobase sequence pair, at least 85%, but not all, of the bases in the contiguous sequence of the first polynucleotide will hybridize to the same number of bases in the contiguous sequence of the second polynucleotide.

[0500] As used herein, the term "sense strand" refers to the strand of a dsRNA that includes a region that is substantially complementary to a region of the antisense strand.

[0501] As used herein, the term "cleavage zone" refers to the region located adjacent to the cleavage site. The cleavage site is the site on the target where cleavage occurs. In some embodiments, the cleavage zone is included in 3 bases adjacent to and on either end of the cleavage site. In some embodiments, the cleavage zone is included in 2 bases adjacent to and on either end of the cleavage site. In some embodiments, the cleavage site is specifically present at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage zone comprises nucleotides 11, 12, and 13.

[0502] As used herein and unless otherwise indicated, the term "complementary" when used to describe a first nucleotide sequence associated with a second nucleotide sequence refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a double helical structure with an oligonucleotide or polynucleotide comprising the second nucleotide sequence under specific conditions, as will be understood by the skilled person. These conditions can, for example, be stringent conditions, wherein stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours, followed by washing. Other conditions can be applied, such as physiologically relevant conditions that can be encountered within an organism. For example, complementary sequences are sufficient to perform the relevant functions of nucleic acids (e.g., RNAi). The skilled person will be able to determine the set of conditions that are most suitable for testing the complementarity of the two sequences based on the ultimate application of the hybridizing nucleotides.

[0503] When there is base pairing in the nucleotide of the first nucleotide sequence and the nucleotide of the second nucleotide sequence over the whole length of the first and second nucleotide sequences, sequences can be "completely complementary" relative to each other. However, when the first sequence is referred to as "substantially complementary" relative to the second sequence in this article, these two sequences can be completely complementary, or they can form one or more by hybridization, but are usually no more than 4, 3 or 2 mismatched base pairs, while retaining the ability to hybridize under the conditions most relevant to their final application. However, when two oligonucleotides are designed to form one or more single-stranded overhangs when hybridization, these overhangs should not be considered as mispairings determined about complementarity. For example, for purposes described herein, a dsRNA like this can also be referred to as "completely complementary": it is that the dsRNA comprises an oligonucleotide of 21 nucleotides and another oligonucleotide of 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides completely complementary to the shorter oligonucleotide.

[0504] As used herein, "complementary" sequences, insofar as they meet the above requirements with respect to their hybridization ability, may also include or be formed entirely from non-Watson-Crick base pairs and / or base pairs formed from non-natural and modified nucleotides. Such non-Watson-Crick base pairs include, but are not limited to, G:U wobble base pairing or Hoogstein base pairing.

[0505] As used herein, the terms "complementary," "fully complementary," and "substantially complementary" can be used with respect to base pairing between the sense and antisense strands of a dsRNA, or between the antisense strand of a dsRNA and a target sequence, as will be understood based on the context of their use.

[0506] As used herein, a polynucleotide that is "substantially complementary to at least a portion of a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion (including the 5'UTR, open reading frame (ORF), or 3'UTR) of an mRNA of interest (e.g., an mRNA encoding CD320 or an mRNA encoding LRP2). For example, a polynucleotide is complementary to at least a portion of a CD320 mRNA or LRP2 mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding CD320 or LRP2.

[0507] As used herein, the term "inhibit" is used interchangeably with "reduce," "silence," "downregulate," "repress," and other similar terms and includes any level of inhibition.

[0508] As used herein, the phrases "inhibit the expression of CD320" and "inhibit the expression of LRP2" include inhibiting the expression of any CD320 or LRP2 gene (e.g., a gene identified from, for example, mouse, rat, monkey, or human), as well as variants (e.g., naturally occurring variants) or mutants of the identified genes. Thus, the CD320 or LRP2 gene can be a wild-type CD320 or LRP2 gene, a mutant CD320 or LRP2 gene, or a transgenic CD320 or LRP2 gene in the context of a genetically manipulated cell, cell group, or organism.

[0509] "Inhibiting the expression of the CD320 gene" or "inhibiting the expression of the LRP2 gene" includes any level of inhibition of the CD320 gene or LRP2 gene, for example, at least partial suppression of CD320 or LRP2 gene expression, such as at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. In a preferred embodiment, inhibition is assessed by expressing the level of CD320 or LRP2 protein in treated cells as a percentage of the mRNA level in control cells using the following formula:

[0510] Normalized protein levels of treated cells / normalized protein levels of control cells. Control cells are negative control siRNA. Normalized means protein levels are normalized to the level of a housekeeping protein.

[0511] The expression of the CD320 or LRP2 gene can be evaluated based on the level of any variable related to CD320 or LRP2 gene expression, e.g., CD320 or LRP2 mRNA levels, CD320 or LRP2 protein levels. Inhibition can be evaluated by a decrease in the absolute or relative level of one or more of these variables compared to a control level. The control level can be any type of control level used in the art, e.g., a pre-dose baseline level or a level determined based on a similar subject, cell, or sample that is untreated or treated with a control (e.g., a buffer-only control or an inactive agent control).

[0512] Contacting a cell with a ds or ss RNAi agent as used herein includes contacting the cell by any possible means, whether in vivo or in vitro. Contacting a cell with an RNAi agent includes contacting the cell with the RNAi agent in vitro or contacting the cell with the RNAi agent in vivo. Contact can be made directly or indirectly. Thus, for example, the RNAi agent can be brought into physical contact with the cell by a separate method, or alternatively, the RNAi agent can be placed in a condition that will allow or cause it to subsequently come into contact with the cell.

[0513] As used herein, "patient" or "subject" is intended to include humans or non-human animals, preferably mammals, e.g., monkeys. Most preferably, the subject or patient is a human.

[0514] As used herein, "CD320-related disease" is intended to include any disease associated with interference with the CD320 gene or protein, polymorphisms, single nucleotide polymorphisms (SNPs), and epigenetic modifications of the CD320 gene. Such diseases can be caused, for example, by excessive production of CD320 protein, by CD320 gene mutations, by abnormal cleavage of CD320 protein, by abnormal folding of CD320 protein, by abnormal interactions between CD320 itself or with other proteins or other endogenous or exogenous substances. For example, cancer can be a CD320-related disease. The degree of inhibition of protein expression can be measured by immunoblotting.

[0515] As used herein, "LRP2-related disease" is intended to include any disease associated with interference with the LRP2 gene or protein, polymorphisms, SNPs, and epigenetic modifications of the CD320 gene. Such diseases can be caused, for example, by overproduction of LRP2 protein, by mutations in the LRP2 gene, by abnormal cleavage of the LRP2 protein, by abnormal folding of the LRP2 protein, or by abnormal interactions between the LRP2 molecule and other proteins or other endogenous or exogenous substances. For example, cancer can be an LRP2-related disease. The degree of inhibition of protein expression can be measured by immunoblotting.

[0516] As used herein, a "therapeutically effective amount" is intended to include an amount of an RNAi agent that, when administered to a cell or patient for the treatment of a CD320-related disease or an LRP2-related disease, is sufficient to affect disease treatment (e.g., by reducing, ameliorating, or maintaining an existing disease or one or more symptoms of the disease, or by preferentially causing the death of diseased cells compared to non-disease cells). A "therapeutically effective amount" may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and history, age, weight, family history, genetic makeup, the stage of the pathological process mediated by CD320 or LRP2 expression, the type of prior or concomitant treatment (if any), and other individual characteristics of the patient to be treated.

[0517] As used herein, a "prophylactically effective amount" is intended to include an amount of an RNAi agent sufficient to prevent or ameliorate one or more symptoms of a disease or pathogen when administered to a subject who has not yet experienced or displayed symptoms of a CD320-related disease or LRP2-related disease, but is susceptible to the disease. Amelioration of a disease includes slowing the progression of a disease or reducing the severity of a subsequent disease. A "prophylactically effective amount" may vary based on the RNAi agent, how the agent is administered, the risk level and history of the disease, age, weight, family history, genetic makeup, type of prior or concomitant treatment (if any), and other individual characteristics of the patient being treated.

[0518] "Therapeutically-effective amount" or "prophylactically effective amount" also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. The RNAi agent used in the methods of the present invention can be administered in an amount sufficient to produce a reasonable benefit / risk ratio applicable to such treatment.

[0519] Pharmaceutical composition

[0520] The methods described herein include administering an LRP2 inhibitory composition and / or a CD320 inhibitory composition, for example, a first siRNA targeting the CD320 gene and / or a second siRNA targeting the LRP2 gene. In some embodiments, the LRP2 inhibitory composition and / or the CD320 inhibitory composition is a pharmaceutical composition.

[0521] The methods described herein also include administration of one or more LRP2 inhibitory compositions and / or one or more CD320 inhibitory compositions, for example, one or more siRNAs targeting the CD320 gene and / or one or more siRNAs targeting the LRP2 gene. It should be understood that these compositions can be chemically modified in a variety of ways and that these modifications do not need to be identical in the composition mixture. In some embodiments, the LRP2 inhibitory composition and / or the CD320 inhibitory composition is a pharmaceutical composition.

[0522] The pharmaceutical compositions of the present invention can be administered in a variety of ways, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical, pulmonary, for example, by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, for example, intraparenchymal, intrathecal, or intraventricular administration.

[0523] Compositions can be delivered in the mode of target specific tissue, such as lung cells, or mammary cells, or brain cells, or bladder cells, or uterine cells, or cervical cells, or prostate cells. Pharmaceutical compositions can be delivered by direct injection into the brain. Injection can be by stereotactic injection into the specific region (for example, substantia nigra, cortex, hippocampus, striatum or globus pallidus) of the brain, or dsRNA can be delivered to multiple regions (for example, multiple regions of the brain, and / or spinal cord) of the central nervous system. DsRNA can also be delivered to the dispersed regions (for example, dispersed delivery to the cortex of the brain) of the brain. Usually, 1) by intratumoral injection, 2) by systemic injection, 3) by the sustained release from the polymer of implantation siRNA is used. Other tissue specificities can be realized by antibody or small molecule conjugation or by tissue-specific delivery device (for example, conduit can be used for delivery to bladder).

[0524] In one embodiment, RNAi targeting LRP2 or CD320 can be delivered through a cannula or other delivery device implanted at one end into the tissue. The cannula can be connected to a reservoir of the RNAi composition. Flow or delivery can be regulated by a pump, such as an osmotic pump or a micropump. In one embodiment, the pump and reservoir are implanted in an area away from the tissue, such as the abdomen, and delivery is implemented by a line leading from the pump or reservoir to the release site.

[0525] Thus, in some embodiments, the pharmaceutical compositions described herein include one or more pharmaceutically acceptable excipients.The pharmaceutical compositions described herein are formulated for administration to a subject.

[0526] As used herein, a pharmaceutical composition or medicament comprises a pharmacologically effective amount of at least one described RNAi agent and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances intentionally included in a drug delivery system in addition to the active pharmaceutical ingredient (API, therapeutic product, e.g., CD320 RNAi agent or LRP2 RNAi agent). Excipients do not exert or are not intended to exert a therapeutic effect at the intended dose. Excipients may function to a) help process the drug delivery system during production, b) protect, support or improve the stability, bioavailability or patient acceptance of the API, c) assist in product identification, and / or d) improve any other properties of the overall safety, effectiveness of the delivery of the API during storage or use. Pharmaceutically acceptable excipients may or may not be inert substances.

[0527] Excipients include, but are not limited to, absorption enhancers, anti-adherents, anti-foaming agents, antioxidants, binders, buffers, carriers, coatings, pigments, delivery enhancers, delivery polymers, dextran, glucose, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, glidants, diluents, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained-release matrices, sweeteners, thickeners, tonicity agents, vehicles, hydrophobic agents, and wetting agents.

[0528] Pharmaceutical compositions suitable for injection can include sterile aqueous solutions (when water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor.RTM.ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). Compositions, including formulations and drug delivery systems, are considered to be stable and should be protected from microorganisms, such as bacteria and fungi, under production and storage conditions. Carriers can be solvents or dispersion media containing (for example) water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol) and their suitable mixtures. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size and by using a surfactant for dispersion. In most cases, isotonic agents, for example, sugars, polyols, such as mannitol, sorbitol and sodium chloride, will preferably be included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0529] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound in a suitable solvent having one or a combination of ingredients listed above, as required, after filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle comprising a basic dispersion medium and other desired ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods include vacuum drying and freeze drying, which provide a powder of the active ingredient plus any other desired ingredients from a previously sterile-filtered solution thereof.

[0530] Formulations suitable for intra-articular administration may be in the form of a sterile aqueous formulation of the drug, which may be in microcrystalline form, for example, a microcrystalline aqueous suspension. Liposomal formulations or biodegradable polymer systems may also be used to provide drugs for intra-articular and ophthalmic administration.

[0531] The active compound can be prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate copolymers, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing these preparations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically available carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0532] Dosage and timing

[0533] The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or condition, previous treatment, the subject's general health and / or age, and the presence of other diseases. In addition, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. As described elsewhere herein, the effective dosage and in vivo half-life of the LRP2 inhibitory compositions and / or CD320 inhibitory compositions encompassed by the present invention can be estimated using conventional methods or based on in vivo testing using appropriate animal models.

[0534] Typically, suitable dosages of pharmaceutical compositions of LRP2 inhibitory compositions and / or CD320 inhibitory compositions will be in the range of 0.01 to 300.0 mg per kg body weight of the recipient per day, typically in the range of 1 to 50 mg per kg body weight per day.

[0535] For example, the LRP2 inhibitory composition and / or the CD320 inhibitory composition can be an siRNA composition of one or more siRNAs and can be administered at 0.01 mg / kg, 0.05 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.628 mg / kg, 2 mg / kg, 3 mg / kg, 5.0 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, 400 mg / kg per single dose. In another embodiment, the dosage is between 0.15 mg / kg and 0.3 mg / kg. For example, the LRP2 and / or CD320 inhibitory composition can be administered at a dose of 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, or 0.3 mg / kg. In one embodiment, the LRP2 and / or CD320 inhibitory composition is administered at a dose of 0.3 mg / kg.

[0536] The pharmaceutical composition can be administered once daily, or once or twice every 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. Dosage units can be mixed for delivery over several days, for example, using conventional sustained-release formulations that provide sustained release of the LRP2 inhibitory composition and / or CD320 inhibitory composition over a period of several days. Sustained-release formulations are well known in the art and are particularly useful for delivering agents to specific sites, such as can be used with the agents described herein.

[0537] In one embodiment, the LRP2-inhibitory composition and / or CD320-inhibitory composition is administered at a dose of 0.3 mg / kg depending on the tumor cell line, and wherein the dose is administered once every 21 days. In another embodiment, the effective amount is 0.3 mg / kg and is administered once every 21 days by infusion at 1 mL / min for 15 minutes, followed by a 70-minute infusion at 3 mL / min for 55 minutes. In another embodiment, the effective amount is 0.3 mg / kg and is administered twice every 21-28 days by infusion at 3.3 mL / min for 60 minutes, or by infusion at 1.1 mL / min for 15 minutes, followed by a 70-minute infusion at 3.3 mL / min for 55 minutes.

[0538] For treatment, the dosage of the LRP2 inhibitory composition and / or the CD320 inhibitory composition can be adjusted.

[0539] The LRP2-inhibitory composition and / or the CD320-inhibitory composition can be administered in combination with other known agents effective in the treatment of pathological processes mediated by target gene expression.

[0540] In another embodiment, the pharmaceutical composition is formulated for administration according to the dosage regimen described herein, e.g., no more than once every 4 weeks, no more than once every 3 weeks, no more than once every two weeks, or no more than once a week. In another embodiment, administration of the pharmaceutical composition can be maintained for one month or longer, e.g., 1, 2, 3, or 6 months or one year or longer.

[0541] In embodiments of the pharmaceutical compositions described herein, the RNAi (e.g., dsRNA) is administered with a buffered solution. In embodiments, the buffered solution comprises acetate, citrate, prolamin, carbonate, or phosphate, or any combination thereof. In embodiments, the buffered solution is phosphate buffered saline (PBS).

[0542] In embodiments of the pharmaceutical compositions described herein, the compositions are administered intravenously.

[0543] In an embodiment of the pharmaceutical compositions described herein, the composition is administered subcutaneously.

[0544] In certain embodiments, a pharmaceutical composition, e.g., a composition described herein, comprises a lipid formulation. In embodiments, the composition is administered intravenously.

[0545] In some embodiments, a pharmaceutical composition, e.g., a composition described herein, includes a cationic polyamine formulation or nanoparticles (e.g., JetPEI). In some embodiments, the composition is administered intravenously.

[0546] In another embodiment, the pharmaceutical composition is formulated for administration according to the dosage regimen described herein, e.g., no more than once every 4 weeks, no more than once every 3 weeks, no more than once every two weeks, or no more than once a week. In another embodiment, administration of the pharmaceutical composition can be maintained for one month or longer, e.g., 1, 2, 3, or 6 months or one year or longer.

[0547] In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 or CD320, is administered with a non-RNAi therapeutic agent, such as an agent known to treat cancer, such as lung cancer. In another embodiment, a composition containing an RNAi agent featured in the invention, e.g., a dsRNA targeting LRP2 and / or CD320, is administered with a non-RNAi therapeutic regimen, such as radiation therapy, chemotherapy, immunotherapy, photodynamic therapy, or a combination thereof.

[0548] In one aspect, provided herein is a method for inhibiting the expression of LRP2 and / or CD320 in a cell, the method comprising: (a) introducing an RNAi agent (e.g., dsRNA) described herein into the cell; and (b) maintaining the cell of step (a) for a sufficient period of time to obtain degradation of mRNA transcripts of the LRP2 gene and / or CD320 gene, thereby inhibiting the expression of the LRP2 gene and / or CD320 gene in the cell.

[0549] In one aspect, provided herein are methods for reducing or inhibiting expression of the LRP2 gene and / or CD320 gene in a cell. The method comprises: (a) introducing one or more complementary double-stranded ribonucleic acid (dsRNA) molecules into a cell, wherein one sequence is designated as the sense strand and the other sequence is designated as the antisense strand, and wherein the antisense strand has substantial complementarity to a portion of an mRNA encoding LRP2 or CD320. The complementary region is 15-30 nucleotides in length, and typically 19-24 nucleotides in length, and upon entry into a cell expressing LRP2 and / or CD320, the dsRNA inhibits expression of the LRP2 protein and / or CD320 protein by at least 10%, e.g., at least 20%, at least 30%, at least 40%, or more; and (b) treating the cell with the dsRNA as described in section (a) once or repeatedly to maintain inhibition of LRP2 and / or CD320 protein expression by at least 10%, e.g., at least 20%, at least 30%, at least 40%, or more, for a desired period of time.

[0550] In embodiments of the above methods for inhibiting LRP2 and / or CD320 expression in cells, the cells are treated ex vivo, in vitro, or in vivo. In embodiments, the cells are melanoma, glioblastoma, lung cancer, triple-negative breast cancer, renal cancer, pancreatic cancer, hepatocellular carcinoma, ovarian cancer, and prostate cancer.

[0551] In some embodiments, the cell is present in a subject in need of treatment, prevention, and / or management of a CD320-associated disease or an LRP2-associated disease.

[0552] In embodiments, expression of LRP2 and / or CD320 is inhibited by at least 30%.

[0553] In embodiments, the IC of an RNAi (eg, dsRNA) 50 In the range of 0.01-50nM.

[0554] In embodiments, the IC of an RNAi (eg, dsRNA) 50 In the range of 0.01-1 nM.

[0555] In certain embodiments, the cell is a mammalian cell (eg, a human, non-human primate, or rodent cell).

[0556] In one embodiment, the cells are treated ex vivo, in vitro, or in vivo (eg, the cells are present in a subject (a patient in need of treatment, prevention, and / or management of a disorder associated with LRP2 and / or CD320 expression)).

[0557] In one embodiment, the subject is a mammal (eg, a human) at risk for or diagnosed with a proliferative disorder.

[0558] In an embodiment, the RNAi (eg, dsRNA) is formulated as a lipid nanoparticle (LNP) polyplex (polyamine) formulation.

[0559] In embodiments, the RNAi (eg, dsRNA) is administered at a dose of 0.05001-500.01 mg / kg.

[0560] In embodiments, the RNAi (eg, dsRNA) is administered at a concentration of 0.01 mg / kg to 50.1 mg / kg of the subject's body weight.

[0561] In an embodiment, the RNAi (eg, dsRNA) is formulated as a LNP formulation and administered at a dose of 0.050.1-50.5 mg / kg.

[0562] In embodiments, the IC of an RNAi (eg, dsRNA) 50 In the range of 0.01-10nM.

[0563] In an embodiment, RNAi (e.g., dsRNA) or a composition comprising RNAi is administered according to a dosage administration regimen. In an embodiment, RNAi (e.g., dsRNA) or a composition comprising RNAi is administered as a single dose or with multiple doses, e.g., according to a dosage administration regimen.

[0564] As used herein, the term "sample" comprises a collection of fluids, cells or tissues separated from an experimenter and fluids, cells or tissues present in an experimenter. Examples of biological fluids include blood, serum and serosal fluid, blood plasma, cerebrospinal fluid, ocular fluid, lymph, urine, saliva, etc. Tissue samples can include samples from tissues, organs or local regions. For example, samples can derive from fluids or cells in specific organs, organ parts or those organs. In some embodiments, samples can derive from tumors. In a preferred embodiment, "sample deriving from an experimenter" refers to blood or blood plasma extracted from an experimenter. In other embodiments, "sample deriving from an experimenter" refers to a tissue biopsy deriving from an experimenter.

[0565] In one embodiment, the characteristic RNAi herein (e.g., dsRNA) comprises a first sequence of a dsRNA selected from the sense sequences of Table 1 and a second sequence selected from the corresponding antisense sequences of Table 1. It should be understood that the suffix A (e.g., OSC17A) represents the antisense strand, while the suffix S (e.g., OSC17S) represents the sense strand. In those cases when we refer to an siRNA without a suffix (e.g., OSC17), we are referring to a dsRNA comprising the antisense and sense strands corresponding to that number (e.g., OSC17A paired with OSC17S).

[0566] In some embodiments, the RNAi is about 15 to about 25 nucleotides in length, and in other embodiments, the RNAi is about 25 to about 30 nucleotides in length. Upon contact with cells expressing CD320, the RNAi targeting CD320 inhibits expression of the CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% or more, as measured by methods described herein. In one embodiment, the RNAi targeting CD320 is formulated in a stable nucleic acid lipid particle (SNALP).

[0567] In some embodiments, the RNAi is about 15 to about 25 nucleotides in length, and in other embodiments, the RNAi is about 25 to about 30 nucleotides in length. Upon contact with a cell expressing LRP2, the RNAi targeting LRP2 inhibits expression of the LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% or more, as measured by methods as described herein. In one embodiment, the RNAi targeting LRP2 is formulated in a stable nucleic acid lipid particle (SNALP).

[0568] In some embodiments, the RNAi is about 15 to about 25 nucleotides in length, and in other embodiments, the RNAi is about 25 to about 30 nucleotides in length. Upon contact with cells expressing CD320, the RNAi targeting CD320 inhibits expression of the CD320 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% or more, as measured by methods described herein. In one embodiment, the RNAi targeting CD320 is formulated as a complex, which can be present as a nanoparticle with a cationic polyamine.

[0569] In some embodiments, the RNAi is about 15 to about 25 nucleotides in length, and in other embodiments, the RNAi is about 25 to about 30 nucleotides in length. Upon contact with a cell expressing LRP2, the RNAi targeting LRP2 inhibits expression of the LRP2 gene by at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% or more, as measured by the methods described herein. In one embodiment, the RNAi targeting LRP2 is formulated as a complex, which can be present as a nanoparticle with a cationic polyamine.

[0570] Reference is now made to Table 1, shRNA sequences used in lentiviral vectors, which shows sequences used to target the CD320 sequence encoding the CD320 protein and the LRP2 sequence encoding the LRP2 protein. The sequences in Table 2 show the DNA that is subsequently transcribed into shRNA, which in turn targets the CD320 or LRP2 mRNA for destruction in cells. Each vector carrying the shRNA coding sequence also contains a unique drug resistance gene, which enables selection of cells that take up the shRNA, as cells that do not take up the shRNA with the unique drug resistance gene will not survive. On day 2, drug selection begins. On day 3, cells are harvested and plated in new culture dishes. Only cells with the drug resistance gene, i.e., cells that have taken up the shRNA viral particles, will survive this re-plating procedure. From day 4 onwards, the growth of each cultured cell is closely observed. As expected, cells infected with an irrelevant control shRNA continue to grow (since the shRNA is essentially non-functional) - data not shown. The results for cell lines that took up CD320+LRP2 shRNA are shown in Table 1 .

[0571] Table 1

[0572]

[0573]

[0574] Preliminary studies showed selective killing of cancer cells by CD320 and LRP2 knockdown, while normal cells were unaffected (Table 2).

[0575] Table 2 shows the effect of simultaneous knockdown of CD320 and LRP2 on cell viability.

[0576] Table 2

[0577]

[0578] Other cancer cell lines were also treated with the compounds described herein to determine whether the cancer cell lines were more sensitive to growth inhibition and toxicity than non-cancerous cells of the same origin. Figure 1 Experimental Summary [ 14 ] Cell lines from skin, prostate, and brain cancers were similarly screened. Table 3 summarizes the effects of simultaneous knockdown of CD320 and LRP2 in cancer and normal cells.

[0579] Table 3

[0580]

[0581]

[0582]

[0583] +++Compared to shSCR (control), cells were not affected

[0584] ++Cells were moderately affected compared to shSCR (control)

[0585] +Compared with shSCR (control), cells were significantly affected

[0586] 0 Compared with shSCR (control), most cells were killed

[0587] Screening results showed that lung, prostate, skin, and brain cancer cell lines were growth-inhibited or killed by simultaneous knockdown of CD320 and LRP2 ("double knockdown"), while non-cancerous cells were unaffected.

[0588] Referring now to FIG2 , representative photographs of cells were taken to document their phenotypes after dual knockdown of CD320 and LRP2 and to demonstrate the sensitivity of cancer cell lines to knockdown of CD320 and LRP2 protein expression.

[0589] Normal cells (GM05659 fibroblasts) or cancer cells were infected with lentivirus expressing control sequence or shRNA of shCD320 and shLRP2, as Figure 1 Cell growth, as shown. Figure 1 Cell images were taken 9 days after lentiviral transfection. Solid ovals represent healthy, growing normal fibroblasts infected with shRNAs targeting CD320 and LRP2. Dashed ovals represent unhealthy, dying cells of a cancer cell line infected with shRNAs targeting CD320 and LRP2.

[0590] Based on the fact that reduced expression of CD320 and LRP2 proteins preferentially leads to adverse effects in cancer cells compared to non-cancerous cells, these results support the use of the compounds as therapeutic agents. Initial experiments were performed using shRNAs delivered via lentiviral vectors. Short inhibitory RNAs (siRNAs) were designed with sequences partially complementary to CD320 and / or LRP2 proteins. siRNAs can be chemically modified to improve their stability and potency and reduce their immunogenicity, and multiple platforms exist for their delivery in clinical applications.

[0591] siRNA sequences that effectively knock down LRP2 and / or CD320 protein levels were designed and identified. Table 4 lists siRNA sequences complementary to CD320 or LRP2 mRNA that were tested for their ability to knock down CD320 or LRP2 protein, respectively (see Figures 3, 4, 5, 12, and 15).

[0592] Table 4

[0593]

[0594]

[0595] The list of all possible siRNA sequences is quite large. We have identified 340 possible siRNA sequences for LRP2 and 59 possible siRNA sequences for CD320 (for a complete list, see Tables 5 and 6, and Tables 5A and 6A identify the target position and the sequence complementary to each identified antisense sequence). In addition, these siRNA sequences can be chemically modified to improve their stability and reduce their off-target effects. siRNA molecules are vulnerable to metabolic degradation, for example, by RNases or DNA enzymes. Chemical modification of siRNA molecules by incorporating one or more non-natural (i.e., artificial) nucleotides within the sequence can impart siRNA tolerance to this metabolic degradation and increase their biological half-life in cells or in plasma. In addition, the inclusion of artificial nucleotides at strategic positions within the siRNA sequence can reduce the immunogenicity of the siRNA and improve the selectivity of the guide strand relative to the passenger strand. The modified siRNA molecule can introduce a single type of artificial nucleotide or can include multiple different types of artificial nucleotides. Artificial nucleotides may include, but are not limited to, those containing chemical modifications to the ribose moiety or to the phosphate moiety ( FIG. 19 and Table 7 ). Examples of artificial nucleotides include, but are not limited to, the structures shown in Table 7 . Furthermore, modifications of multiple structural elements may be combined. Furthermore, modifications may be made to the nucleobase B, and in addition to the natural RNA nucleobases (G, C, A, U), modifications may include non-natural bases such as those containing sulfur atoms (e.g., thiouracil).

[0596] Table 7. Corresponding to Figure 19A Nucleotide modification

[0597] <![CDATA[Name a > Y X Z R R’ B (nucleobase) [2fN] O O O F H G, C, A, U, other 2'-FANA O O O H F G, C, A, U, other [mN] O O O OMe H G, C, A, U, other 2'-MOE O O O <![CDATA[CH2CH2OMe]]> H G, C, A, U, other 2'-EA O O O <![CDATA[CH2CH2NH2]]> H G, C, A, U, other 2'-DMEA O O O <![CDATA[CH2CH2NMe2]]> H G, C, A, U, other 2'-DMAP O O O <![CDATA[CH2CH2CH2NMe2]]> H G, C, A, U, other *As in N1*N2 O S O OH H G, C, A, U, other **As in N1**N2 S S O OH H G, C, A, U, other 2'-deoxy O O O H H G, C, A, U, other 4’-S O O S H H G, C, A, U, other F-SRNA O O S F H G, C, A, U, other Me-SRNA O O S OMe H G, C, A, U, other 4'-S-FANA O O S H F G, C, A, U, other

[0598] a N represents any ribonucleotide or deoxyribonucleotide or an analog thereof.

[0599] In some embodiments, the phosphodiester group that covalently links two nucleotides is chemically modified such that, for example, one or both oxygen atoms in the group are replaced by sulfur atoms, as indicated by a single or double asterisk between the two nucleotides to indicate that one or both oxygen atoms in the phosphodiester are replaced by sulfur (Tables 7 and Figure 19A In some embodiments, the siRNA sequence may include other artificial nucleotides in which the ribose moiety has been further structurally modified, such as by the addition of carbon atoms covalently linked to the ribose moiety 2' and 5' ( Figure 19B -C) or the bridging atom between positions 1' and 2' of the ribose moiety ( Figure 19D ), or alternatively, a change in the size of the sugar ring in a given nucleotide, for example, deletion of the bond between carbons 2' and 3' of the ribose moiety ( Figure 19E ) or increase the sugar ring size from 5 to 6 atoms ( Figure 19F -G).

[0600] Table 5 CD320

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609] Table 6 LRP2

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632] Table 5A CD320 antisense targets

[0633]

[0634]

[0635]

[0636]

[0637] Table 6A LRP2 antisense targets

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649] In some embodiments, the antisense strand (indicated by "A" in the OS ID name) and / or the sense strand (indicated by "S" in the OS ID name) of the RNAi agent comprises or consists of a nucleobase sequence, for example, "OSC17A-1" CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17), and the nucleobase sequence may include at least one or more nucleotides as modified nucleotides, and wherein SEQ ID NO: 17 is located at positions 1 to 25 (5'→3') of the antisense strand and forms a duplex with the corresponding sense strand (indicated as OSC17S-1). In some embodiments, the antisense strand of the RNAi agent comprises or consists of a nucleobase sequence (e.g., CAGUUGCGCAGUUUCUUGUCAGUUC[dT][dT] (SEQ ID NO: 17)), wherein all or substantially all or 1, 2, 3, 4, or 5 nucleotides are modified nucleotides (see, e.g., SEQ ID NO. 24), and wherein SEQ ID NO: 24 is located at positions 1 to 27 (5'→3') of the antisense strand. For any antisense or sense strand disclosed herein, in some embodiments, the antisense strand of the RNAi agent comprises or consists of the sequence (5'→3'), wherein * is a phosphorothioate bond between deoxythymines [dT]; and / or wherein mC, mA, mG, and mU are 2'-O-methylcytidine, 2'-O-methyladenine, 2'-O-methylguanosine, and 2'-O-methyluridine, respectively; and / or wherein 2fA, 2fU, 2fG, and 2fC are 2'-fluoroadenine, 2'-fluorouridine, 2'-fluoroguanosine, and 2'-fluorocytosine, respectively. The antisense targets on the mRNA are designated by the same name, but without "A" or "S" after the name. Antisense sequences with the same name, for example, OSC17A-1 to OSC17A-18, bind to the same nucleotide target sequence.

[0650] The sequences shown in Table 4 were transfected into HEK 293 (human embryonic kidney) and MDA-MB-435S (human melanoma) cell lines to determine their ability to reduce protein expression of LRP2 and CD320 genes / proteins. These two cell lines were selected due to their relatively high expression levels of LRP2, as referenced in the Human Protein Atlas at proteinatlas.org and the NCI-60 gene expression profiles at discover.nci.nih.gov / cellminer / , allowing for easy detection of changes in LRP2 protein expression.

[0651] Reference Figure 3A -B and Figure 3D-E, HEK293 and MDA-MB-231 cells were transfected with 20 nM of the indicated siRNAs and incubated for 48 hours. Whole cell lysates were prepared and immunoblotted for CD320 and LRP2 protein levels. Protein levels were normalized to a housekeeping control gene unaffected by siRNA transfection. The figure shows the fold change in protein levels compared to a scrambled siRNA control (OSS1). (Means - + SEM are shown, n = 3).

[0652] CD320 and LRP2 protein levels were determined by immunoblotting and quantified using Image Studio Software (LiCor Company) relative to control proteins not affected by CD320 or LRP2 knockdown. To determine knockdown efficacy, CD320 ( Figure 3A -B) and LRP2( Figure 3D -E) were compared with the levels in untreated and scrambled sense controls (black and gray bars, respectively, in all panels of Figure 3). We found that two siRNA sequences targeting CD320 (OSC17 and OSC47) almost completely abolished the expression of CD320 ( Figure 3A -circles in B). siLRP2 sequences resulted in different efficiencies in reducing LRP2 protein. In both cell lines, two sequences (OSL231 and OSL245) consistently reduced LRP2 levels by 75% or more ( Figure 3B , circle of E).

[0653] Reference Figure 6 Lysates were prepared from transformed (HEK293) and representative cancer cell lines and immunoblotted to determine LRP2 protein levels. The selected cancer cells exhibited low LRP2 expression levels. Results represent the mean + SEM of three independent lysates. The data demonstrate that the selected cancer cells exhibited very low LRP2 expression levels.

[0654] We transfected a panel of LRP2 and CD320 siRNAs into cancer cell lines derived from various tissues and analyzed the levels of LRP2 and CD320 proteins in the cell lines. In an experimental design similar to that described for HEK293 and MDA-MB-435S cells, representative cell lines from prostate, breast, and glioblastoma, as well as normal fibroblasts, were exposed to siRNAs against CD320 and LRP2. Figure 3C ,F and the results are shown in Fig. 4.

[0655] Reference Figure 3C , F; and Figure 4, as for Figure 3A , B, D, and E, MDA-MB-231LnCAP, MCF-7, and U251 cells were exposed to siRNA sequences to knock down CD320 ( Figure 3C and Figure 4A -C) and LRP2( Figure 3F and Figure 4D -F). For all cell lines tested, compared to untreated or scrambled controls, Figure 3C and Figure 4A CD320 protein knockdown was greater than 90% in LnCAP cells. LRP2 knockdown was also achieved in all cell lines. However, the knockdown level was lower in LnCAP cells compared to the other cell lines, and the effective sequence may also be different ( Figure 3F and Figure 4D -F).

[0656] Referring now to FIG5 , an experimental design similar to that described in FIG3 was used. Additional prostate and brain cancer cell lines and normal fibroblasts were exposed to siRNA directed against CD320. CD320 levels in DU-145 (prostate) cells were near knockdown, while knockdown levels in A172 brain cells and normal fibroblasts were 21%-33% and 25%-28%, respectively ( Figure 5A -C).

[0657] From these studies, we can conclude that two siRNAs against CD320 (OSC17 and OSC47) very effectively knocked down CD320 protein levels (80% or more) in almost every cell line tested. Although LRP2 is theoretically more difficult to knock down due to its size, we have identified two siRNAs, OSL231 and OSL245, that consistently knocked down LRP2 in most cell lines in which we could detect LRP2.

[0658] Additionally, in HEK 293 cells, LRP2 protein expression levels were high and readily detectable by immunoblotting. As measured by immunoblotting, cancer cell lines had much lower LRP2 expression ( Figure 6 ), and some cell lines may contain levels of LRP2 below which they can be reliably detected.

[0659] Referring now to Figure 7, the effect of doxorubicin treatment on cell viability as measured by the CTG assay is shown. A172 and HCC15 cells were plated in 96-well plates at 1200 cells / well. The following day, cells were treated with the indicated concentrations of doxorubicin. Four days after the start of doxorubicin exposure, the viability of the cells was determined using the CTG assay. The line represents the calculated IC 50Instead of visually assessing the effect of knockdown of CD320 / LRP2 gene expression on cell proliferation (as shown in FIG2 for shRNA-mediated knockdown of CD320 / LRP2), a functional assay was developed to quantify the effect of simultaneous knockdown of LRP2 and CD320 on cell viability by siRNA. A widely used assay for cell viability measurement is the Promega Cell-titer The ATP level in the quantified cells was measured using a TECAN luminescent microplate reader (CTG) with a quantified ATP level in the cells (viable cells produce ATP, while dead cells do not). After the cells were cultured with the CTG reagent, the ATP level was indirectly measured using a TECAN luminescent microplate reader as light generation. As a first step, the toxicity of the known chemotherapeutic drug doxorubicin was determined for the cell lines of interest. In our assay, doxorubicin was used as a positive control for cytotoxicity. Figure 7 shows the ATP level in A172 brain cancer cells ( Figure 7A ) and HCC15 lung cancer cells ( Figure 7B Based on this data, the IC values of doxorubicin treatment on these cell lines were determined. 50 Based on these findings, a larger screen was initiated to determine the IC of doxorubicin in several cancer and non-cancer cell lines. 50 , thereby determining the dosage of doxorubicin to be used when the cell lines are used in a viability assay testing simultaneous knockdown of CD320 and LRP2. 50 The results for the cell lines tested are summarized in the determinations.

[0660] In order to quantify the effect of knockdown of CD320 and LRP2 on cell proliferation, cells were plated in 24-well plates. The next day, cells were transfected with siRNA for CD320 and / or LRP2. For effective toxicity, cell lines may require repeated transfections and / or time (cell line dependent). In this experimental design, there is still room for repeated infection, and some cell lines should be required for effective toxicity. At the end of the study, cell growth of the cell lines was analyzed by CTG assay. Figure 8 A schematic diagram of this experimental design is shown.

[0661] Table 8

[0662]

[0663] Cell lines were plated at 1,000 to 4,000 cells / well in 96-well plates and treated with doxorubicin on the following days. CTG activity was measured 4 days after treatment. IC was calculated using GraphPad Prism software. 50 The results are summarized in Table 8.

[0664] These data show that doxorubicin works effectively on the CTG platform (i.e., doxorubicin kills cancer cells) and can therefore be used as a positive control in in vitro assays to compare the siRNA-knockdown cytotoxic effects of CD320 and LRP2. In this latter assay, similar to the experiments providing the data for Figures 3, 4, and 5, normal or cancer cells were transfected with siRNA sequences specifically targeting CD320 or LRP2, either alone or in combination, or with control siRNA. In Figures 3, 4, and 5, protein levels were measured, but in in vitro assays, cell viability was measured.

[0665] Reference Figure 8 , shows an overview of a functional assay for screening the effects of (ds) siRNA on cell proliferation. In order to quantify the effects of knockdown of CD320 and LRP2 on cell proliferation, cells were plated in 24-well plates. The next day, cells were transfected with siRNA for CD320 and / or LRP2. For effective toxicity, cell lines may require repeated transfections and / or time (cell line dependent). In this experimental design, there is still room for repeated infection, and some cell lines should be required for effective toxicity. At the end of the study, cell growth of the cell lines was analyzed by CTG assay.

[0666] Reference Figure 10B , MDA-MB-231 triple-negative breast cancer cells were plated in 24-well plates at 20,000 cells / well. The next day, cells were transfected with 20 nM of siRNA selected from OSC17, OSC47, OSL231, and OSL245. Cells were also transfected with a combination of two siRNAs (one of which targets CD320 and the other targets LRP2) at 10 nM, wherein the siRNA targeting CD320 was selected from OSC17 and OSC47, and the LRP2 targeting siRNA was selected from OSL231 and OSL245, administered at a dose of 10 nM, respectively. As indicated in Table 9, cells were transfected 4 times over the course of 11 days. On day 11, cell growth was analyzed by CTG assay. Cell survival percentages compared to non-targeted controls (OSS2) are shown. The data shown are the mean values- / +SEM of 6 experiments.

[0667] 11, MDA-MB-231 and DU-145 cells were transfected with 20 nM negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (OSL245). Cells were also transfected with a combination of siRNA targeting CD320 (OSC17) and siRNA targeting LRP2 (OSL24) at concentrations ranging from 2 to 20 nM, such that the concentrations of both siRNAs equaled 20 nM of total transfected siRNA, as shown in FIG11. Cells were repeatedly transfected as shown in Table 9, and the percentage of cell survival is shown.

[0668] Referring now to FIG12 , MDA-MB-231 breast cancer cells were transfected with 20 nM negative control siRNA (OSS2), 20 nM siRNA targeting CD320 (OSC17), or 20 nM siRNA targeting LRP2 (OSL245). Lysates were prepared daily for 5 days. Figure 12A ) or LRP2 protein levels ( Figure 12B ), and the lysates were subjected to immunoblotting.

[0669] Referring now to Figures 9 and 10, data are shown that quantify the effects of CD320 and LRP2 knockdown in various cell lines. Representative cell lines of several cancer types or normal fibroblasts were transfected with siRNAs targeting CD320 or LRP2, alone or in combination, as indicated. For potent toxicity, cells were repeatedly transfected as listed in Table 9, and viability was determined by the CTG assay. In our assay, doxorubicin-treated cells were used as a positive control for cytotoxicity.

[0670] The data from each of the experiments shown in Figures 9 and 10 and the other cell lines we screened are summarized in Table 9. These experiments demonstrate the broad applicability of siCD320 and siLRP2 cytotoxicity across multiple cancer types.

[0671] Reference Figure 13 , shows a schematic diagram of PEI and siRNA complex. PEI and siRNA are mixed together. Subsequently, the polyplex (nanoparticle, broadly speaking) form of the PEI-siRNA complex can enter the cell through endocytosis or pinocytosis mechanism.

[0672] Reference Figure 14siRNA is a short RNA double helix of usually 16 to 30 nucleotides; the sequence of siRNA is complementary to the mRNA expressed in the cell. The exogenous siRNA double helix is introduced into the cell by transfection. The siRNA double helix is unwound by the RISC (RNA-induced silencing complex) complex, so that the guide strand of the siRNA hybridizes with its complementary mRNA molecule. The mRNA is degraded by the RISC / AGO complex, which has RNase cleavage activity. The end result is that the mRNA targeted by the siRNA is degraded and the protein encoded by the mRNA is not produced. Compared with the control treated cells, this results in a "knockdown" effect or reduced protein level of the gene targeted by the siRNA.

[0673] With reference now to Figure 15, the effectiveness of INTERFERin in delivering siRNA to cancer cells has been shown. According to the manufacturer's regulations, 2nM indicated siRNA was transfected into A172 and MDA-MB-435S cells. Cell lysates were prepared 3 days after infection, and CD320 protein levels were analyzed by immunoblotting. OSS1 and OSS2 are non-targeted siRNA controls. In this experiment, two sequences were tested. Compared with OSS1, for A172 cells, CD320 protein levels were knocked down to 9% to 18%, and for MDA-MB-435S cells, they were knocked down to 26% to 48%. When other transfection reagents (e.g., RNAiMAX, Viromer Blue) used in the experiments previously specifically described for MDA-MB-435S cells were used to deliver siRNA, a more effective knockdown of CD320 was observed. Polyplus INTERFERin platform has been tested in vitro in a proof-of-principle experiment in our laboratory, so that siRNA can be delivered to target cells in vitro by the platform.

[0674] Referring now to Figure 16, there is shown treatment of breast, prostate, and skin cancer cells with a CD320 receptor inhibitor or an LRP2 receptor inhibitor, or a combination of both, in an amount effective for inhibiting cancer cell proliferation, compared to control cells treated with a control siRNA. MDA-MB-231, DU145, LnCAP, and MDA-MB-435S cells were plated in 24-well plates at 20,000 cells per well. The next day, cells were transfected with 20 nM of the indicated siRNA to knock down CD320, LRP2, or a scrambled control. For the combination of siRNAs, cells were treated with 10 nM of each siRNA (20 nM total treatment). As shown in Table 9, cells were repeatedly transfected for the length of time indicated in Table 9. At the end of the experiment, the indicated cell photos were collected.

[0675] Table 9. Summary of functional siRNA data screening

[0676]

[0677]

[0678]

[0679] Note: Values represent percentage survival compared to the negative control OSS2.

[0680] A murine human tumor xenograft model was established using triple-negative breast cancer cells (MDA-MB-231) injected into the flanks of nude mice to test the efficacy of combined dosing of OSC17 and OSL245. Drug administration was performed by repeated dosing within a range of drug concentrations using intratumoral, IV, IP, or dedicated routes of administration. Dosage schedules were based on pilot studies to determine the tolerability of the delivery vehicle and drug and were incorporated into the range taught in the art. Delivery platforms include nanoparticles, liposomes, micelles, polymers, small molecule conjugates, aptamers, and antibody conjugates. Composite technologies containing elements of the above delivery systems are also known.

[0681] The production method consists of synthesizing two single-stranded oligonucleotides of the duplex by conventional solid-phase oligonucleotide synthesis. After purification, the two oligonucleotides are annealed to form a duplex.

[0682] in vivo It is a cationic polymer delivery system that binds negatively charged siRNA molecules to cationic polyamine polymers. Its ip and intratumoral use have been reported in xenograft models using MCF-7 (breast), MDA-MB-231 (breast) and A549 (lung) cell lines. This delivery system is currently used in 7 human clinical trials (Table 10). It is reported that the siRNA prepared is very stable.

[0683] Table 10 - In vivo Clinical trials using

[0684]

[0685] Note that in the specification and claims, "about" or "approximately" means within twenty percent (20%) of the numerical amount cited. Although the present invention has been described in detail with specific reference to these embodiments, other embodiments can achieve the same results. For example, antisense oligonucleotides complementary to target mRNA can inhibit the expression of the protein of interest, although the antisense oligonucleotides are not provided as dsRNA and the antisense oligonucleotides may not bind to the RISC / AGO complex. Changes and modifications of the present invention will be apparent to those skilled in the art, and it is intended that all such modifications and equivalent forms be covered in the appended claims. The entire disclosures of all references, patent applications, patents, and patent publications cited above are incorporated herein by reference. Sequence Listing <110> BIOAFFINITY TECHNOLOGIES, INC. <120> Compositions and methods for treating cancer <130> 32064-1035-PCT <140> <141> <150> 62 / 785,315 <151> 2018-12-27 <160> 956 <170> PatentIn version 3.5 <210> 1 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 1 ucuuaucccu gcgcacgcgc att 23 <210> 2 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 2 ucucuuaucc cugcgcacgc gtt 23 <210> 3 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 3 augcuguccc cacagcggcg ctt 23 <210> 4 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 4 auccaaccgc cgcucaugcu gtt 23 <210> 5 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 5 uggaaagcgg gcucgcggcg gtt 23 <210> 6 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 6 aacuuggugg gugggcacga gtt 23 <210> 7 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 7 uggaacuugg ugggugggca ctt 23 <210> 8 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 8 acuggaacuu gguggguggg ctt 23 <210> 9 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 9 uaagccacug gugcggcacu gtt 23 <210> 10 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 10 acgcauaagc cacuggugcg gtt 23 <210> 11 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 11 uccaaguccc ugucgcagcg ctt 23 <210> 12 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 12 uccucaucgc ugccaucgcu gtt 23 <210> 13 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 13 ucacugacgc cggugcaggg gtt 23 <210> 14 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 14 uugucaguuc ccccagagca gtt 23 <210> 15 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 15 uucuugucag uucccccaga gtt 23 <210> 16 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 16 aguuucuugu caguuccccc att 23 <210> 17 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 17 caguugcgca guuucuuguc aguuctt 27 <210> 18 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 18 caguugcgca guuucuuguc aguuctt 27 <210> 19 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 19 caguugcgca guuucuuguc aguuctt 27 <210> 20 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 20 caguugcgca guuucuuguc aguuctt 27 <210> twenty one <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> twenty one caguugcgca guuucuuguc aguuc 25 <210> twenty two <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> twenty two caguugcgca guuucuuguc aguuc 25 <210> twenty three <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> twenty three caguugcgca guuucuuguc aguuctt 27 <210> twenty four <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> twenty four caguugcgca guuucuuguc aguuctt 27 <210> 25 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 25 caguugcgca guuucuuguc aguuc 25 <210> 26 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 26 caguugcgca guuucuuguc aguuctt 27 <210> 27 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 27 caguugcgca guuucuuguc aguuc 25 <210> 28 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 28 caguugcgca guuucuuguc aguuctt 27 <210> 29 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 29 caguugcgca guuucuuguc aguuc 25 <210> 30 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 30 caguugcgca guuucuuguc aguuctt 27 <210> 31 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 31 caguugcgca guuucuuguc aguuctt 27 <210> 32 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 32 caguugcgca guuucuuguc aguuctt 27 <210> 33 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 33 caguugcgca guuucuuguc agu 23 <210> 34 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 34 caguugcgca guuucuuguc agu 23 <210> 35 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 35 augcagucau cgcucagcgu gtt 23 <210> 36 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 36 aaugcaguca ucgcucagcg utt 23 <210> 37 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 37 uggaaugcag ucaucgcuca gtt 23 <210> 38 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 38 aguggaaugc agucaucgcu ctt 23 <210> 39 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 39 acagucuggg uggccgucgc att 23 <210> 40 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 40 auugguucca cagccgagcu ctt 23 <210> 41 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 41 ucucauuggu uccacagccg att 23 <210> 42 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 42 aucucauugg uuccacagcc gtt 23 <210> 43 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 43 aggaucucau ugguuccaca gtt 23 <210> 44 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 44 ugagagaggu gacacucucc att 23 <210> 45 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 45 ugguuguggc auuccugaga gtt 23 <210> 46 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 46 uggcauuccc gacagagggg att 23 <210> 47 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 47 aggauguggc auucccgaca gtt 23 <210> 48 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 48 uuccagacug gucuccggca gtt 23 <210> 49 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 49 auaaccccau aggcaguugg gtt 23 <210> 50 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 50 uugcacugag caccgcagca gtt 23 <210> 51 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 51 aaaaggagga ggguggcggu gtt 23 <210> 52 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 52 acaaaaggag gaggguggcg gtt 23 <210> 53 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 53 accaguaacc ccagugggcg gtt 23 <210> 54 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 54 uucauggcca ccaguaaccc ctt 23 <210> 55 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 55 acuccuucau ggccaccagu att 23 <210> 56 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 56 uucugacagc agcagggacu ctt 23 <210> 57 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 57 ucuguucuga cagcagcagg gtt 23 <210> 58 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 58 ucuucuguuc ugacagcagc att 23 <210> 59 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 59 aggucuucug uucugacagc att 23 <210> 60 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 60 uuguccucag ggcagcgagg utt 23 <210> 61 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 61 aagugcuugu ccucagggca gtt 23 <210> 62 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 62 uacccauccg caucacugcu ctt 23 <210> 63 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 63 ucucugaggg cuggugugcc ctt 23 <210> 64 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 64 aagagcucag gucucugagg gtt 23 <210> 65 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 65 aagagcucag gucucugagg gtt 23 <210> 66 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 66 aagagcucag gucucugagg gtt 23 <210> 67 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 67 aagagcucag gucucugagg gtt 23 <210> 68 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 68 aagagcucag gucucugagg g 21 <210> 69 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 69 aagagcucag gucucugagg g 21 <210> 70 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 70 aagagcucag gucucugagg gtt 23 <210> 71 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 71 aagagcucag gucucugagg gtt 23 <210> 72 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 72 aagagcucag gucucugagg g 21 <210> 73 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 73 aagagcucag gucucugagg gtt 23 <210> 74 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 74 aagagcucag gucucugagg g 21 <210> 75 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 75 aagagcucag gucucugagg gtt 23 <210> 76 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 76 aagagcucag gucucugagg g 21 <210> 77 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 77 aagagcucag gucucugagg g 21 <210> 78 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 78 aagagcucag gucucugagg gtt 23 <210> 79 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 79 aagagcucag gucucugagg gtt 23 <210> 80 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 80 aagagcucag gucucugagg gtt 23 <210> 81 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 81 aagagcucag gucucugagg g 21 <210> 82 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 82 aagagcucag gucucugagg gtt 23 <210> 83 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 83 agaagagcuc aggucucuga gtt 23 <210> 84 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 84 auagggagug uccagggacc ctt 23 <210> 85 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 85 uccauaggga guguccaggg att 23 <210> 86 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 86 aucuccauag ggagugucca gtt 23 <210> 87 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 87 ucaguucugg cuguggcagg utt 23 <210> 88 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 88 uucuaccccc ugggagcugc ctt 23 <210> 89 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 89 aagcacaggg ccguucuacc ctt 23 <210> 90 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 90 ugucuuaagc acagggccgu utt 23 <210> 91 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 91 agugucuuaa gcacagggcc gtt 23 <210> 92 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 92 uuuuuugagg augugaagca att 23 <210> 93 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 93 uuuuuuugag gaugugaagc att 23 <210> 94 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 94 agagaauagg gacgcgugcg ctt 23 <210> 95 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 95 cgagagaaua gggacgcgug ctt 23 <210> 96 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 96 aguacgacag gggugucgcc gtt 23 <210> 97 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 97 gguagguugg cggcgaguac gtt 23 <210> 98 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 98 ccaccuuucg cccgagcgcc gtt 23 <210> 99 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 99 ccuugaacca cccacccgug ctt 23 <210> 100 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 100 ugaccuugaa ccacccaccc gtt 23 <210> 101 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 101 cgugaccuug aaccacccac ctt 23 <210> 102 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 102 guauucggug accacgccgu gtt 23 <210> 103 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 103 cgugcguauu cggugaccac gtt 23 <210> 104 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 104 ucagguucag ggacagcguc gtt 23 <210> 105 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 105 ggaggaguag cgacgguagc gtt 23 <210> 106 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 106 ucagugacug cggccacguc ctt 23 <210> 107 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 107 agaacaguca agggggucuc gtt 23 <210> 108 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 108 caaagaacag ucaagggggu ctt 23 <210> 109 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 109 cgucaaagaa cagucaaggg gtt 23 <210> 110 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 110 gaacugacaa gaaacugcgc aacugtt 27 <210> 111 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 111 gaacugacaa gaaacugcgc aacugtt 27 <210> 112 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 112 gaacugacaa gaaacugcgc aacugtt 27 <210> 113 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 113 gaacugacaa gaaacugcgc aacug 25 <210> 114 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 114 gaacugacaa gaaacugcgc aacugtt 27 <210> 115 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 115 gaacugacaa gaaacugcgc aacug 25 <210> 116 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 116 gaacugacaa gaaacugcgc aacugtt 27 <210> 117 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 117 gaacugacaa gaaacugcgc aacugtt 27 <210> 118 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 118 gaacugacaa gaaacugcgc aacugtt 27 <210> 119 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 119 gaacugacaa gaaacugcgc aacug 25 <210> 120 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 120 gaacugacaa gaaacugcgc aacug 25 <210> 121 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 121 gaacugacaa gaaacugcgc aacugtt 27 <210> 122 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 122 gaacugacaa gaaacugcgc aacug 25 <210> 123 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 123 ugacaagaaa cugcgcaacu gtt 23 <210> 124 <211> 17 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 124 gaaacugcgc aacugtt 17 <210> 125 <211> 17 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 125 gaaacugcgc aacugtt 17 <210> 126 <211> 15 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 126 gaaacugcgc aacug 15 <210> 127 <211> 15 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 127 gaaacugcgc aacug 15 <210> 128 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 128 cuuacgucag uagcgagucg ctt 23 <210> 129 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 129 ccuuacguca guagcgaguc gtt 23 <210> 130 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 130 ucaccuuacg ucaguagcga gtt 23 <210> 131 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 131 acucaccuua cgucaguagc gtt 23 <210> 132 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 132 ccugucagac ccaccggcag ctt 23 <210> 133 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 133 aguaaccaag gugucggcuc gtt 23 <210> 134 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 134 cuagaguaac caaggugucg gtt 23 <210> 135 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 135 ccuagaguaa ccaagguguc gtt 23 <210> 136 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 136 ccuccuagag uaaccaaggu gtt 23 <210> 137 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 137 ggacucucuc cacugugaga gtt 23 <210> 138 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 138 guaccaacac cguaaggacu ctt 23 <210> 139 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 139 acaccguaag ggcugucucc ctt 23 <210> 140 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 140 ccuccuacac cguaagggcu gtt 23 <210> 141 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 141 cgaaggucug accagaggcc gtt 23 <210> 142 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 142 guuauugggg uauccgucaa ctt 23 <210> 143 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 143 cgaacgugac ucguggcguc gtt 23 <210> 144 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 144 uguuuuccuc cucccaccgc ctt 23 <210> 145 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 145 ccuguuuucc uccucccacc gtt 23 <210> 146 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 146 gguggucauu ggggucaccc gtt 23 <210> 147 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 147 ggaaguaccg guggucauug gtt 23 <210> 148 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 148 ccugaggaag uaccgguggu ctt 23 <210> 149 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 149 acaagacugu cgucgucccu gtt 23 <210> 150 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 150 gaagacaaga cugucgucgu ctt 23 <210> 151 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 151 ccagaagaca agacugucgu ctt 23 <210> 152 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 152 gcuccagaag acaagacugu ctt 23 <210> 153 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 153 cgaacaggag ucccgucgcu ctt 23 <210> 154 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 154 cguucacgaa caggaguccc gtt 23 <210> 155 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 155 ccauggguag gcguagugac gtt 23 <210> 156 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 156 ccagagacuc ccgaccacac gtt 23 <210> 157 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 157 cccucagaga ccugagcucu utt 23 <210> 158 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 158 cccucagaga ccugagcucu utt 23 <210> 159 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 159 cccucagaga ccugagcucu utt 23 <210> 160 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 160 cccucagaga ccugagcucu u 21 <210> 161 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 161 cccucagaga ccugagcucu utt 23 <210> 162 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 162 cccucagaga ccugagcucu u 21 <210> 163 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 163 cccucagaga ccugagcucu utt 23 <210> 164 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 164 cccucagaga ccugagcucu utt 23 <210> 165 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 165 cccucagaga ccugagcucu utt 23 <210> 166 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 166 cccucagaga ccugagcucu u 21 <210> 167 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 167 cccucagaga ccugagcucu u 21 <210> 168 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 168 cccucagaga ccugagcucu utt 23 <210> 169 <211> twenty one <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 169 cccucagaga ccugagcucu u 21 <210> 170 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 170 cccucagaga ccugagcucu utt 23 <210> 171 <211> 17 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 171 gagaccugag cucuutt 17 <210> 172 <211> 17 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 172 gagaccugag cucuutt 17 <210> 173 <211> 15 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 173 gagaccugag cucuu 15 <210> 174 <211> 15 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 174 gagaccugag cucuu 15 <210> 175 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 175 ucuucucgag uccagagacu ctt 23 <210> 176 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 176 ggucuucucg aguccagaga ctt 23 <210> 177 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 177 gguaucccuc acaggucccu gtt 23 <210> 178 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 178 agagguaucc cucacagguc ctt 23 <210> 179 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 179 ccuagaggua ucccucacag gtt 23 <210> 180 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 180 ggagucaaga ccgacaccgu ctt 23 <210> 181 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 181 gcaagauggg ggacccucga ctt 23 <210> 182 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 182 aauucguguc ccggcaagau gtt 23 <210> 183 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 183 ucacagaauu cgugucccgg ctt 23 <210> 184 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 184 ccucacagaa uucguguccc gtt 23 <210> 185 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 185 aaaaaaaacu ccuacacuuc gtt 23 <210> 186 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 186 aaaaaaaaac uccuacacuu ctt 23 <210> 187 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 187 uacuuuguga gcaaucuuga ctt 23 <210> 188 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 188 auucacuugg gauacacuga ctt 23 <210> 189 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 189 acaugaaaac ucauugugca att 23 <210> 190 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 190 ucuuuacagu caucuucucc att 23 <210> 191 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 191 uaucuuuaca gucaucuucu ctt 23 <210> 192 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 192 aacauuuaug aacaucauga gtt 23 <210> 193 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 193 ucacaaacuu uauaaaugga gtt 23 <210> 194 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 194 aucacaaacu uuauaaaugg att 23 <210> 195 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 195 auacuacagu auuuuccggu att 23 <210> 196 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 196 ucauacuaca guauuuuccg gtt 23 <210> 197 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 197 acaaauuccc cauaucuggc att 23 <210> 198 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 198 aagauauacc cuucuucaca gtt 23 <210> 199 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 199 uuagcuuugc aauacugucc att 23 <210> 200 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 200 aucauuagcu uugcaauacu gtt 23 <210> 201 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 201 aaaggaauca uuagcuuugc att 23 <210> 202 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 202 augaauauca ccaauuaaca att 23 <210> 203 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 203 aaaaaaccuu auuuugcacg gtt 23 <210> 204 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 204 ugaaaaaacc uuauuuugca ctt 23 <210> 205 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 205 aaugucaacu gaaaaaaccu utt 23 <210> 206 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 206 uaaugucaac ugaaaaaacc utt 23 <210> 207 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 207 uuaaaccauu aaugucaacu gtt 23 <210> 208 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 208 uauuuaaacc auuaauguca att 23 <210> 209 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 209 uagauuuuau uauuaaccca gtt 23 <210> 210 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 210 auagauuuua uuauuaaccc att 23 <210> 211 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 211 aaauuuacca uaucuaugcg gtt 23 <210> 212 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 212 aaguuuucag uuauaagggu att 23 <210> 213 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 213 aauaaauaac caacaguugg gtt 23 <210> 214 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 214 agaaaaauaa auaaccaaca gtt 23 <210> 215 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 215 auaucauauc cagaguuacc ctt 23 <210> 216 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 216 aguuucaaug uaaucaaacc gtt 23 <210> 217 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 217 uuacaguuuc aauguaauca att 23 <210> 218 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 218 auaaguuaca guuucaaugu att 23 <210> 219 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 219 ucuuuacacg gauugguagc att 23 <210> 220 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 220 aaaaucaauc ccgacaaaga att 23 <210> 221 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 221 ucugaaaaaa agauagugcu gtt 23 <210> 222 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 222 aucugaaaaa aagauagugc utt 23 <210> 223 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 223 aaaaaucaug uguuuugaca utt 23 <210> 224 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 224 uuugcuuaaa aaucaugugu utt 23 <210> 225 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 225 aacuuucaac auuuuccacc ctt 23 <210> 226 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 226 uugaaaucca aucaaaagcc att 23 <210> 227 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 227 uuugaaaucc aaucaaaagc ctt 23 <210> 228 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 228 uagagauucu uugaaaucca att 23 <210> 229 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 229 auagagauuc uuugaaaucc att 23 <210> 230 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 230 uuuaaauacu gaacuacugu gtt 23 <210> 231 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 231 uauuuaaaua cugaacuacu gtt 23 <210> 232 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 232 auagauaccc ggcaaaagga utt 23 <210> 233 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 233 aagaguagug uuuauuacag gtt 23 <210> 234 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 234 aucaaaauag gcaucuaccc att 23 <210> 235 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 235 ucaauuuuau caaaauaggc att 23 <210> 236 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 236 uaaaugcucu ccaaagaugg ctt 23 <210> 237 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 237 ucaaaugcag uauguaagca att 23 <210> 238 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 238 uucaaaugca guauguaagc att 23 <210> 239 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 239 ugauuacagg cguuagaacc att 23 <210> 240 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 240 uguuaucaug acaaucaucg att 23 <210> 241 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 241 uuaucacagg uguauugggu gtt 23 <210> 242 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 242 auuaucacag guguauuggg utt 23 <210> 243 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 243 aguucuuuga gauacacugg utt 23 <210> 244 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 244 ucgaauugca guucuuuuca utt 23 <210> 245 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 245 ucaauacauc gaugauuggg gtt 23 <210> 246 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 246 aacgauaggu caauacaucg att 23 <210> 247 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 247 acaaacgaua ggucaauaca utt 23 <210> 248 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 248 ucaaaaacac caucacaacg att 23 <210> 249 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 249 ucacauuccc agaaguucgg gtt 23 <210> 250 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 250 aucacauucc cagaaguucg gtt 23 <210> 251 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 251 ugaugaaggg caagucuugg gtt 23 <210> 252 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 252 agaaucauug gcaaguaaga att 23 <210> 253 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 253 uaucacauuc aucuaugucu utt 23 <210> 254 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 254 aauaucacau ucaucuaugu ctt 23 <210> 255 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 255 aacauguagc cuguaucaca ctt 23 <210> 256 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 256 ucacuuucua acauguagcc utt 23 <210> 257 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 257 aucacuuucu aacauguagc ctt 23 <210> 258 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 258 aauguaagaa ccauucucga ctt 23 <210> 259 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 259 uacaauguaa gaaccauucu ctt 23 <210> 260 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 260 aaaaucaaca gcuacaaugu att 23 <210> 261 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 261 auugaaucaa aaucaacagc utt 23 <210> 262 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 262 uaauugaauc aaaaucaaca gtt 23 <210> 263 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 263 aagauacgac cacuaauuga att 23 <210> 264 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 264 aguuucaguc aagaugaugc utt 23 <210> 265 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 265 aauaguuuca gucaagauga utt 23 <210> 266 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 266 uauugcaaua guuucaguca att 23 <210> 267 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 267 ucuauugcaa uaguuucagu ctt 23 <210> 268 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 268 aaucuauugc aauaguuuca gtt 23 <210> 269 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 269 auuuuggaga cuucaauugu utt 23 <210> 270 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 270 uuagguuuuu acuaaucagc att 23 <210> 271 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 271 ucauucuggg aucuaaugcu att 23 <210> 272 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 272 uucauucugg gaucuaaugc utt 23 <210> 273 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 273 aguagaugcu cauucauucu gtt 23 <210> 274 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 274 auuauaauca caaaagucca utt 23 <210> 275 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 275 uccauuauaa ucacaaaagu ctt 23 <210> 276 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 276 ugccguauaa ucaaaucact t 21 <210> 277 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 277 auauuauaca uuacaacuga ctt 23 <210> 278 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 278 auugaauauu auacauuaca att 23 <210> 279 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 279 aauuugguug uuucgaagga utt 23 <210> 280 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 280 acggaauuug guuguuucga att 23 <210> 281 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 281 uuacaguuau uaagaaaggu utt 23 <210> 282 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 282 uccaaaaauu auauguugcc utt 23 <210> 283 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 283 uuccaaaaau uauauguugc ctt 23 <210> 284 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 284 ucuaaaccau ucuguauccc utt 23 <210> 285 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 285 aucuaaacca uucuguaucc ctt 23 <210> 286 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 286 uucaacaucu aaaccauucu gtt 23 <210> 287 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 287 auuuucaacc caauagaugu att 23 <210> 288 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 288 uauagaagca aauacugucc utt 23 <210> 289 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 289 uagauauaga agcaaauacu gtt 23 <210> 290 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 290 uaaggccagg uucauagaag gtt 23 <210> 291 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 291 ucuugaaauc caaucuaagg ctt 23 <210> 292 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 292 auaaagguuu cuugaaaucc att 23 <210> 293 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 293 ucaaaaccuc gauugacuga gtt 23 <210> 294 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 294 uucuguaucu gauaucuccg utt 23 <210> 295 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 295 uuucuguauc ugauaucucc gtt 23 <210> 296 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 296 uuuuucugua ucugauaucu ctt 23 <210> 297 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 297 aucaauguuu uucuguaucu gtt 23 <210> 298 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 298 auaaaggaaa gaaucaugga ctt 23 <210> 299 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 299 aauaaaggaa agaaucaugg att 23 <210> 300 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 300 ucaguauaau aaaggaaaga att 23 <210> 301 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 301 uuucaaugac cucauacugu utt 23 <210> 302 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 302 auuuggaaca uuaucucuca att 23 <210> 303 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 303 agauuuggaa cauuaucucu ctt 23 <210> 304 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 304 ucagauuugg aacauuaucu ctt 23 <210> 305 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 305 uugcuacagc cauuugaggt t 21 <210> 306 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 306 augaaagagu uauauggaga gtt 23 <210> 307 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 307 acaaugaaag aguuauaugg att 23 <210> 308 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 308 ugaaacaaca augaaagagu utt 23 <210> 309 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 309 auugaaacaa caaugaaaga gtt 23 <210> 310 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 310 agcuaaagcc ucugauugca gtt 23 <210> 311 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 311 aagcuaaagc cucugauugc att 23 <210> 312 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 312 acaauuccaa gcuaaagccu ctt 23 <210> 313 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 313 ugacaauucc aagcuaaagc ctt 23 <210> 314 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 314 ugaaugaucu gacaauucca att 23 <210> 315 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 315 auguucauca gagaagaucc att 23 <210> 316 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 316 uauuccaugu gucacaaugu utt 23 <210> 317 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 317 acuucuauca guguuucaga att 23 <210> 318 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 318 uauugauccg cagaacuucu att 23 <210> 319 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 319 uguucuuggg aucuacaaca att 23 <210> 320 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 320 aaagaacgcu caaucuuugg utt 23 <210> 321 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 321 uaaacguagc caucacuucg gtt 23 <210> 322 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 322 aucuaaagaa ucaucaaccc att 23 <210> 323 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 323 uuauaucuaa agaaucauca att 23 <210> 324 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 324 auagaauuuu caaaaacagu gtt 23 <210> 325 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 325 ugauagaauu uucaaaaaca gtt 23 <210> 326 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 326 uuucaaauuc cuaucuaccc att 23 <210> 327 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 327 uuuucaaauu ccuaucuacc ctt 23 <210> 328 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 328 auauugucuc uuaucacugu gtt 23 <210> 329 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 329 ugauauuguc ucuuaucacu gtt 23 <210> 330 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 330 ugaaauggca caauucuugc ctt 23 <210> 331 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 331 uguugaaaug gcacaauucu utt 23 <210> 332 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 332 aauuuucugu ugaaauggca ctt 23 <210> 333 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 333 aaauuuucug uugaaauggc att 23 <210> 334 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 334 auuagacaag gcaaagauga gtt 23 <210> 335 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 335 acauuuauug uuuggaaagg utt 23 <210> 336 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 336 aucacuuaca cugucauagu ctt 23 <210> 337 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 337 uagauucuau cacuuacacu gtt 23 <210> 338 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 338 aguagauucu aucacuuaca ctt 23 <210> 339 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 339 uuuuguguga aguagauucu att 23 <210> 340 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 340 uaaauuuugu gugaaguaga utt 23 <210> 341 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 341 ucuaguaauc cagucaaagg ctt 23 <210> 342 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 342 aauucuucua guaauccagu ctt 23 <210> 343 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 343 uaaauucuuc uaguaaucca gtt 23 <210> 344 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 344 auaaauucuu cuaguaaucc att 23 <210> 345 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 345 auauacuggc cauagagagu ctt 23 <210> 346 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 346 uucuuugugu guacaaguca gtt 23 <210> 347 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 347 aauucuuugu guguacaagu ctt 23 <210> 348 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 348 ucgguaaauu cuuugugugu att 23 <210> 349 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 349 uguuacacug uuguuucugg utt 23 <210> 350 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 350 auuguuacac uguuguuucu gtt 23 <210> 351 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 351 aaacuguuca caaggauugu utt 23 <210> 352 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 352 acaucguuca ccauugucca ctt 23 <210> 353 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 353 uguuauugca cauaaacucc gtt 23 <210> 354 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 354 ucuguuauug cacauaaacu ctt 23 <210> 355 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 355 uuaugacauu uuguguaucc att 23 <210> 356 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 356 ugaauuauga cauuuugugu att 23 <210> 357 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 357 uuugaauuau gacauuuugu gtt 23 <210> 358 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 358 uacaaauauu ugaauuauga ctt 23 <210> 359 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 359 aaauaaacgc gaggaauaca att 23 <210> 360 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 360 aauaaguagg guuuucauca ctt 23 <210> 361 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 361 ucacaauacc aauguugagg att 23 <210> 362 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 362 uguuucuuga ucacaauacc att 23 <210> 363 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 363 aacaaucugu uucuugauca ctt 23 <210> 364 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 364 uuuacacaga gaaacucgga att 23 <210> 365 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 365 auuuacacag agaaacucgg att 23 <210> 366 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 366 uucugauucu caucguagcc gtt 23 <210> 367 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 367 auuuucagag caaguucucc utt 23 <210> 368 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 368 auaucuuugg gauacacagu ctt 23 <210> 369 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 369 agguaaacug auucuguugg ctt 23 <210> 370 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 370 auagaaacug guuaaggugu ctt 23 <210> 371 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 371 acaauagaaa cugguuaagg utt 23 <210> 372 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 372 ucaucaauau caacacaagu ctt 23 <210> 373 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 373 agauguagga gccuauuaca utt 23 <210> 374 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 374 ucgauguuac uguuuugccg gtt 23 <210> 375 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 375 uugcuaaaaa ugagauaggg utt 23 <210> 376 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 376 auuucucaaa uaguaacggu utt 23 <210> 377 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 377 aauuucucaa auaguaacgg utt 23 <210> 378 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 378 aaauuucuca aauaguaacg gtt 23 <210> 379 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 379 aguuaaauuu cucaaauagu att 23 <210> 380 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 380 aucuauaguu aaauuucuca att 23 <210> 381 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 381 uaaaaauagc caucuauagu utt 23 <210> 382 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 382 aucuaaugcc acaacauugu ctt 23 <210> 383 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 383 aauccaauac aaucucuucu ctt 23 <210> 384 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 384 acauucucuc aaugacuugc ctt 23 <210> 385 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 385 augauugucu ccuuguuugu ctt 23 <210> 386 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 386 auuaucacag acuuguuggu utt 23 <210> 387 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 387 uucaaaaaug guaauagcga att 23 <210> 388 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 388 ucuucaaaaa ugguaauagc gtt 23 <210> 389 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 389 auuuguuucc cuuuuccacu gtt 23 <210> 390 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 390 auuugaucca ucauauuugu utt 23 <210> 391 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 391 uauauggaug guacacaugg att 23 <210> 392 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 392 aaagaagacg gucuucauca gtt 23 <210> 393 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 393 ugaauucugu gaaguuguca ctt 23 <210> 394 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 394 acaaugucca cuuguacacu gtt 23 <210> 395 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 395 acacaauguc cacuuguaca ctt 23 <210> 396 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 396 uuuuugcauu cgaacauagu att 23 <210> 397 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 397 augguuuuug cauucgaaca utt 23 <210> 398 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 398 auacaaacau gguuuuugca utt 23 <210> 399 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 399 aucacauuuc caauauggcg gtt 23 <210> 400 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 400 ugaaguucuu caucugaacc att 23 <210> 401 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 401 auaaaugcag cgauuguugu ctt 23 <210> 402 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 402 auucuguaca agguuuaggg gtt 23 <210> 403 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 403 uauucuguac aagguuuagg gtt 23 <210> 404 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 404 auucauauuc uguacaaggu utt 23 <210> 405 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 405 uauucauauu cuguacaagg utt 23 <210> 406 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 406 uuauauucau auucuguaca att 23 <210> 407 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 407 uauugcaacc caguucaucg gtt 23 <210> 408 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 408 auauuuucag cacauguucu utt 23 <210> 409 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 409 uuaauugggu acaauuuugc utt 23 <210> 410 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 410 aaaaacauug guuucgaacc ctt 23 <210> 411 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 411 ugucaaaaac auugguuucg att 23 <210> 412 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 412 uucgaauucg gacauuguca gtt 23 <210> 413 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 413 auuauauuuu cgaauucgga ctt 23 <210> 414 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 414 agauuauauu uucgaauucg gtt 23 <210> 415 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 415 ucaucuugaa gauacucuga gtt 23 <210> 416 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 416 uauauuccuc aucuugaaga utt 23 <210> 417 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 417 uuugauagca ccaaaccuag agccctt 27 <210> 418 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 418 uuugauagca ccaaaccuag agccctt 27 <210> 419 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 419 uuugauagca ccaaaccuag agccctt 27 <210> 420 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 420 uuugauagca ccaaaccuag agccctt 27 <210> 421 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 421 uuugauagca ccaaaccuag agccc 25 <210> 422 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 422 uuugauagca ccaaaccuag agccc 25 <210> 423 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 423 uuugauagca ccaaaccuag agccctt 27 <210> 424 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 424 uuugauagca ccaaaccuag agccctt 27 <210> 425 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 425 uuugauagca ccaaaccuag agccc 25 <210> 426 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 426 uuugauagca ccaaaccuag agccctt 27 <210> 427 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 427 uuugauagca ccaaaccuag acccc 25 <210> 428 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 428 uuugauagca ccaaaccuag agccctt 27 <210> 429 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 429 uaucaaaccu cgauagcaac accgc 25 <210> 430 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 430 uuugauagca ccaaaccuag agccctt 27 <210> 431 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 431 uuugauagca ccaaaccuag agccctt 27 <210> 432 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 432 uuugauagca ccaaaccuag agccctt 27 <210> 433 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 433 uuugauagca ccaaaccuag agc 23 <210> 434 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 434 uuugauagca ccaaaccuag agc 23 <210> 435 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 435 ucaaaguugg ggauguaggc att 23 <210> 436 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 436 ucaguuucag gucaacuucc utt 23 <210> 437 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 437 uacguauuuc aguuucaggu ctt 23 <210> 438 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 438 uuacguauuu caguuucagg utt 23 <210> 439 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 439 aguuuagcca ccucaaugcg utt 23 <210> 440 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 440 aacauaagcc cuaguuuggg att 23 <210> 441 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 441 ucgauuuuag guuccuuucc ctt 23 <210> 442 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 442 ucgaaaacca ggauguugcg gtt 23 <210> 443 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 443 ucaaauaauc gauagaaagg ctt 23 <210> 444 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 444 uuguucaaau aaucgauaga att 23 <210> 445 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 445 uuaugguuuc aauaacgucc utt 23 <210> 446 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 446 uuuuaugguu ucaauaacgu ctt 23 <210> 447 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 447 auuuuauggu uucaauaacg utt 23 <210> 448 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 448 uuugcaauga cucuccuauc agucctt 27 <210> 449 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 449 uuugcaauga cucuccuauc agucctt 27 <210> 450 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 450 uuugcaauga cucuccuauc agucctt 27 <210> 451 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 451 uuugcaauga cucuccuauc agucctt 27 <210> 452 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 452 uuugcaauga cucuccuauc agucc 25 <210> 453 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 453 uuugcaauga cucuccuauc agucc 25 <210> 454 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 454 uuugcaauga cucuccuauc agucctt 27 <210> 455 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 455 uuugcaauga cucuccuauc agucctt 27 <210> 456 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 456 uuugcaauga cucuccuauc agucc 25 <210> 457 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 457 uuugcaauga cucuccuauc agucctt 27 <210> 458 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 458 uuugcaauga cucuccuauc acucc 25 <210> 459 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 459 uuugcaauga cucuccuauc agucctt 27 <210> 460 <211> 25 <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 460 uauccuaagu cacacguuug acugc 25 <210> 461 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 461 uuugcaauga cucuccuauc agucctt 27 <210> 462 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 462 uuugcaauga cucuccuauc agucctt 27 <210> 463 <211> 27 <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 463 uuugcaauga cucuccuauc agucctt 27 <210> 464 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 464 uuugcaauga cucuccuauc agu 23 <210> 465 <211> twenty three <212> RNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <400> 465 uuugcaauga cucuccuauc agu 23 <210> 466 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 466 uagauaucca guauaacugg utt 23 <210> 467 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis Oligonucleotides <220> <223> Description of combined DNA / RNA molecules: Synthesis Oligonucleotides <400> 467 uuuuguuucc auacuucucc ctt 23 <210> 468 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> Descripti...

Claims

1. A double-stranded RNA interference (RNAi) reagent comprising: a mixture of (i) and (ii), (i) a first double-stranded ribonucleic acid (dsRNA) for inhibiting CD320 gene expression, wherein the first dsRNA comprises a sense strand and an antisense strand that form a duplex, (ii) a second dsRNA for inhibiting LRP2 gene expression, wherein the second dsRNA comprises a sense strand and an antisense strand that form a duplex, and wherein the sense strand of the first dsRNA is complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is complementary to the antisense strand of the second dsRNA, wherein, The first dsRNA is any one of OSC17 and OSC47, the second dsRNA is any one of OSL231 and OSL245, the antisense strand sequence of OSC17 is shown in any one of SEQ ID NOs: 17-34, and the sense strand sequence is shown in any one of SEQ ID NOs: 110-127; the antisense strand sequence of OSC47 is shown in any one of SEQ ID NOs: 64-81, and the sense strand sequence is shown in any one of SEQ ID NOs: 157-174; The antisense chain sequence of OSL231 is shown in any one of SEQ ID NOs: 417-434, and the sense chain sequence is shown in any one of SEQ ID NOs: 791-808; the antisense chain sequence of OSL245 is shown in any one of SEQ ID NOs: 448-465, and the sense chain sequence is shown in any one of SEQ ID NOs: 822-839.

2. The double-stranded RNAi reagent according to claim 1, wherein (i) The antisense strand of the first dsRNA includes a region complementary to a CD320 RNA transcript.

3. The double-stranded RNAi reagent according to claim 1, wherein (i) the antisense strand of the first dsRNA is selected from CAGUUGCGCAGUUUCUUGUCAGUUCdTdT (SEQ ID NO: 17); CAGUUGCGCAGUUUCUUGUCAGUUCdT*dT(SEQ ID NO 18); AAGAGCUCAGGUCUCUGAGGGdTdT (SEQ ID NO 64); and AAGAGCUCAGGUCUCUGAGGGdT*dT (SEQ ID NO 65); and (ii) the antisense strand of the second dsRNA is selected from UUUGAUAGCACCAAACCUAGAGCCCdTdT (SEQ ID NO: 417); UUUGAUAGCACCAAACCUAGAGCCCdT*dT(SEQ ID NO:418); UUUGCAAUGACUCUCCUAUCAGUCCdTdT (SEQ ID NO: 448); and UUUGCAAUGACUCUCCUAUCAGUCCdT*dT(SEQ ID NO:449); wherein * is a phosphorothioate bond; and The sense strand is complementary to the antisense strand.

4. The double-stranded RNAi reagent according to claim 1, wherein The first dsRNA comprises a sense strand and an antisense strand forming a duplex, the sequence of the antisense strand being SEQ ID NO: 17 and the sequence of the sense strand being SEQ ID NO: 110, or the sequence of the antisense strand being SEQ ID NO: 18 and the sequence of the sense strand being SEQ ID NO:

111.

5. The double-stranded RNAi reagent according to claim 1, wherein The second dsRNA comprises a sense strand and an antisense strand forming a duplex, the sequence of the antisense strand being SEQ ID NO: 417 and the sequence of the sense strand being SEQ ID NO: 808, or the sequence of the antisense strand being SEQ ID NO: 448 and the sequence of the sense strand being SEQ ID NO:

822.

6. An isolated cell comprising the first dsRNA according to (i) and the second dsRNA according to (ii) of any one of claims 1 to 5. 7 . A pharmaceutical composition for inhibiting the expression of CD320 gene and LRP2 gene, comprising the double-stranded RNAi agent according to any one of claims 1 to 5 and an excipient. The pharmaceutical composition according to claim 7 , wherein the excipient is a carrier.

9. Use of an effective amount of a CD320 inhibitor and an effective amount of an LRP2 inhibitor in the preparation of a medicament for inhibiting cancer cell proliferation, wherein the CD320 inhibitor is a first double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand forming a duplex, and the LRP2 inhibitor is a second dsRNA comprising a sense strand and an antisense strand forming a duplex, wherein the sense strand of the first dsRNA is complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is complementary to the antisense strand of the second dsRNA, wherein: The first dsRNA is any one of OSC17 and OSC47, the second dsRNA is any one of OSL231 and OSL245, the antisense strand sequence of OSC17 is shown in any one of SEQ ID NOs: 17-34, and the sense strand sequence is shown in any one of SEQ ID NOs: 110-127; the antisense strand sequence of OSC47 is shown in any one of SEQ ID NOs: 64-81, and the sense strand sequence is shown in any one of SEQ ID NOs: 157-174; The antisense strand sequence of OSL231 is shown in any one of SEQ ID NOs: 417-434, and the sense strand sequence is shown in any one of SEQ ID NOs: 791 to 808; the antisense strand sequence of OSL245 is shown in any one of SEQ ID NOs: 448-465, and the sense strand sequence is shown in any one of SEQ ID NOs: 822-839; The cancer cells are selected from the group consisting of melanoma, glioblastoma, lung cancer, breast cancer, triple-negative breast cancer and prostate cancer.

10. The use according to claim 9, comprising the first dsRNA and the second dsRNA according to any one of claims 2 to 5.

11. The use according to claim 9, wherein The cancer cells expressed CD320 and LRP2.

12. Use of an inhibitor of CD320 in an amount effective to inhibit or kill cancer cells present in a therapy-resistant cancer and an inhibitor of LRP2 in an amount effective to inhibit or kill cancer cells present in the therapy-resistant cancer in the preparation of a medicament for treating a therapy-resistant cancer in a subject who has previously received therapy, wherein the inhibitor of CD320 is a first double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand that form a duplex, and the inhibitor of LRP2 is a second dsRNA comprising a sense strand and an antisense strand that form a duplex, wherein the sense strand of the first dsRNA is complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is complementary to the antisense strand of the second dsRNA, wherein The first dsRNA is any one of OSC17 and OSC47, the second dsRNA is any one of OSL231 and OSL245, the antisense strand sequence of OSC17 is shown in any one of SEQ ID NOs: 17-34, and the sense strand sequence is shown in any one of SEQ ID NOs: 110-127; the antisense strand sequence of OSC47 is shown in any one of SEQ ID NOs: 64-81, and the sense strand sequence is shown in any one of SEQ ID NOs: 157-174; The antisense strand sequence of OSL231 is shown in any one of SEQ ID NOs: 417-434, and the sense strand sequence is shown in any one of SEQ ID NOs: 791-808; the antisense strand sequence of OSL245 is shown in any one of SEQ ID NOs: 448-465, and the sense strand sequence is shown in any one of SEQ ID NOs: 822-839; The cancer cells are selected from the group consisting of melanoma, glioblastoma, lung cancer, breast cancer, triple-negative breast cancer and prostate cancer.

13. The use according to claim 12, comprising the first dsRNA and the second dsRNA according to any one of claims 2 to 5.

14. The use according to claim 12, wherein Cancer cells of the resistant cancer express CD320 and LRP2.

15. Use of an inhibitor of CD320 in an amount effective to inhibit or kill cancer cells in cancer and an inhibitor of LRP2 in an amount effective to inhibit or kill cancer cells in the cancer in the preparation of a medicament for treating cancer in a subject with recurrent or recurrent cancer, wherein the inhibitor of CD320 is a first double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand that form a duplex, and the inhibitor of LRP2 is a second dsRNA comprising a sense strand and an antisense strand that form a duplex, wherein the sense strand of the first dsRNA is complementary to the antisense strand of the first dsRNA, and the sense strand of the second dsRNA is complementary to the antisense strand of the second dsRNA, wherein The first dsRNA is any one of OSC17 and OSC47, the second dsRNA is any one of OSL231 and OSL245, the antisense strand sequence of OSC17 is shown in any one of SEQ ID NOs: 17-34, and the sense strand sequence is shown in any one of SEQ ID NOs: 110-127; the antisense strand sequence of OSC47 is shown in any one of SEQ ID NOs: 64-81, and the sense strand sequence is shown in any one of SEQ ID NOs: 157-174; The antisense strand sequence of OSL231 is shown in any one of SEQ ID NOs: 417-434, and the sense strand sequence is shown in any one of SEQ ID NOs: 791-808; the antisense strand sequence of OSL245 is shown in any one of SEQ ID NOs: 448-465, and the sense strand sequence is shown in any one of SEQ ID NOs: 822-839; The cancer cells are selected from the group consisting of melanoma, glioblastoma, lung cancer, breast cancer, triple-negative breast cancer and prostate cancer.

16. The use according to claim 15, comprising the first dsRNA and the second dsRNA according to any one of claims 2 to 5.

17. The use according to claim 15, wherein The cancer cells of the relapsed or recurrent cancer express CD320 and LRP2.

18. Use of an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective for inhibiting or killing cancer cells in cancer in the preparation of a medicament for inhibiting the proliferation of cancer cells, wherein the cancer cells are contacted with a composition comprising an inhibitor of CD320 and an inhibitor of LRP2 in an amount effective for inhibiting the proliferation of the cancer cells, wherein: The first dsRNA is any one of OSC17 and OSC47, and the second dsRNA is any one of OSL231 and OSL245, wherein the antisense strand complementary to the CD320 RNA transcript is shown as any one of SEQ ID NOs: 17-34, or any one of SEQ ID NOs: 64-81; and the antisense strand sequence complementary to the LRP2 RNA transcript is shown as any one of SEQ ID NOs: 417-434, or any one of SEQ ID NOs: 448-465, wherein the cancer cell is selected from the group consisting of melanoma, glioblastoma, lung cancer, breast cancer, triple-negative breast cancer, and prostate cancer.

19. The use according to claim 18, wherein The cancer cells expressed CD320 and LRP2.

20. The use according to claim 18, wherein The composition is a mixture comprising: i) a CD320 inhibitor selected from an antibody that binds to CD320, a small molecule inhibitor of CD320, an RNAi agent that hybridizes to a nucleic acid encoding CD320, and any combination thereof, and ii) an LRP2 inhibitor selected from an antibody that binds to LRP2, a small molecule inhibitor of LRP2, an RNAi agent that hybridizes to a nucleic acid sequence encoding LRP2, and any combination thereof, wherein the RNAi agent that hybridizes to mRNA encoding CD320 comprises a first double-stranded ribonucleic acid (dsRNA) for inhibiting CD320 expression, wherein the first dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region complementary to a CD320 RNA transcript, and the RNAi agent that hybridizes to mRNA encoding LRP2 comprises a second dsRNA for inhibiting LRP2 expression, wherein the second dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises a region complementary to an LRP2 RNA transcript.

Images