MYC NUCLEIC ACIDS AND USES THEREOF
Disclosed herein are molecules and pharmaceutical compositions that mediate RNA interference against MYC. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that mediate RNA interference against MYC.
1 . A polynucleic acid molecule that mediates RNA interference against MYC, wherein the polynucleic acid molecule comprises at least 80% sequence identity to a sequence selected from SEQ ID NOs: 1-12, wherein the polynucleic acid molecule hybridizes to a MYC target sequence with less than 4 mismatched bases, wherein the polynucleic acid molecule comprises at least one 2′ modified nucleotide, at least one modified internucleotide linkage, or at least one inverted abasic moiety, and wherein the polynucleic acid molecule is from about 10 to about 50 nucleotides in length.
2 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-12.
3 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule hybridizes to a MYC target sequence with less than 3 mismatched bases, less than 2 mismatched bases, or less than 1 mismatched bases.
4 . The polynucleic acid molecule of claim 1 , wherein the at least one 2′ modified nucleotide comprises 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl, 2′-deoxy, T-deoxy-2′-fluoro, 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), T-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), or 2′-O—N-methylacetamido (2′-O-NMA) modified nucleotide.
5 . The polynucleic acid molecule of claim 1 , wherein the at least one 2′ modified nucleotide comprises locked nucleic acid (LNA) or ethylene nucleic acid (ENA).
6 . The polynucleic acid molecule of claim 1 , wherein the at least one inverted basic moiety is at at least one terminus.
7 . The polynucleic acid molecule of claim 1 , wherein the at least one modified internucleotide linkage comprises a phosphorothioate linkage or a phosphorodithioate linkage.
8 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule is from about 10 to about 30 nucleotides in length.
9 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule is at least 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length.
10 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises at least one of: from about 5% to about 100% modification, from about 10% to about 100% modification, from about 20% to about 100% modification, from about 30% to about 100% modification, from about 40% to about 100% modification, from about 50% to about 100% modification, from about 60% to about 100% modification, from about 70% to about 100% modification, from about 80% to about 100% modification, and from about 90% to about 100% modification.
11 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, or more modified nucleotides.
12 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule further hybridizes to a second polynucleotide to form a double-stranded polynucleic acid molecule.
13 . The polynucleic acid molecule of claim 12 , wherein the second polynucleotide comprises at least one modification.
14 . The polynucleic acid molecule of claim 12 , wherein the second polynucleotide comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-12.
15 . The polynucleic acid molecule of claim 1 , wherein the polynucleic acid molecule is RNA.
16 . The polynucleic acid molecule of claim 1 , wherein MYC is c-MYC gene, L-MYC gene, or N-MYC gene.
17 . The polynucleic acid molecule of claim 1 , wherein MYC is c-MYC gene.
18 . A pharmaceutical composition comprising:
a) a molecule of claim 1 ; and
b) a pharmaceutically acceptable excipient.
19 . The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is formulated as a nanoparticle formulation.
20 . The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is formulated for parenteral, oral, intranasal, buccal, rectal, or transdermal administration.
21 . A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a composition comprising a molecule of claim 1 .
22 . The method of claim 21 , wherein the disease or disorder is a cancer.
23 . The method of claim 22 , wherein the cancer comprises a MYC-associated cancer.
24 . The method of claim 22 , wherein the cancer comprises bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma multiforme, head and neck cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, or thyroid cancer.
25 . The method of claim 22 , wherein the cancer comprises acute myeloid leukemia, CLL, DLBCL, or multiple myeloma.
26 . A method of inhibiting the expression of MYC gene in a primary cell of a patient, comprising administering a molecule of claim 1 to the primary cell.
27 . The method of claim 26 , wherein the method is an in vivo method.
28 . The method of claim 26 , wherein the patient is a human.