Compositions and methods for gene silencing
View Patent ↗Compositions and methods for modulating the expression of a protein of interest are provided.
1. A method of treating a disease or disorder in a subject, said method comprising administering at least one composition comprising at least one U1 adaptor for inhibiting the expression of at least one gene and at least one pharmaceutically acceptable carrier,
wherein said U1 adaptor is a nucleic acid molecule comprising an annealing domain operably linked to at least one effector domain, wherein said annealing domain hybridizes to the pre-mRNA of said gene, and wherein said effector domain hybridizes to the U1 snRNA of U1 snRNP.
2. The method of claim 1 , wherein said annealing domain is about 10 to about 30 nucleotides in length.
3. The method of claim 1 , wherein said effector domain is about 8 to about 20 nucleotides in length.
4. The method of claim 1 , wherein said effector domain and annealing domain are linked by a bond.
5. The method of claim 1 , wherein said effector domain and annealing domain are linked by a linker domain of about 1 to about 10 nucleotides.
6. The method of claim 1 , wherein said effector domain comprises the sequence 5′-CAGGUAAGUA-3′ (SEQ ID NO: 1).
7. The method of claim 1 , wherein said effector domain comprises the sequence 5′-CAGGUAAGUAU-3′ (SEQ ID NO: 32).
8. The method of claim 1 , wherein said effector domain comprises the sequence 5′-GCCAGGUAAGUAU -3′ (SEQ ID NO: 33).
9. The method of claim 1 , wherein said U1 adaptor comprises at least one nucleotide analog.
10. The method of claim 9 , wherein said nucleotide analog is 2′-O-methylnucleotides.
11. The method of claim 9 , wherein said nucleotide analog is a phosphorothioate.
12. The method of claim 1 , wherein said annealing domain hybridizes with a target sequence in the 3′ terminal exon of the gene.
13. The method of claim 1 , wherein the effector domain is operably linked to the 3′ end of the annealing domain, the 5′ end of the annealing domain, or both the 5′ and 3′ end of the annealing domain.
14. The method of claim 1 , comprising the administration of more than one U1 adaptor.
15. The method of claim 1 , further comprising the administration of at least one siRNA or antisense oligonucleotide.
16. The method of claim 1 , wherein said nucleic acid molecule is contained within a delivery vehicle.
17. The method of claim 16 , wherein said delivery vehicle is selected from the group consisting of liposomes, nanoparticles, and polymeric composition.
18. The method of claim 17 , wherein said delivery vehicle is a dendrimer.
19. The method of claim 1 , wherein said disease or disorder is a viral, bacterial, or fungal infection.
20. The method of claim 1 , wherein said disease or disorder is selected from the group consisting of hypercholesterolemia, diabetes, inflammatory disease, Parkinson's disease, and neurological disease.
21. The method of claim 1 , wherein said disease or disorder is hypercholesterolemia.
22. The method of claim 21 , wherein said gene is PCSK9.
23. The method of claim 1 , wherein said disease or disorder is diabetes and said gene is selected the group consisting of Fas (CD95), protein tyrosine phosphatase 1B (PTP-1B), and T cell protein tyrosine phosphatase (TCPTP).
24. The method of claim 1 , wherein said disease or disorder is an inflammatory disease and said gene is tumor necrosis factor α (TNFα).
25. The method of claim 1 , wherein said disease or disorder is Parkinson's disease and said gene is α-synuclein.
26. The method of claim 1 , wherein said disease or disorder is a neurological disease and said gene is amyloid precursor protein (APP) or β-secretase.