Selective inhibition of polyglutamine protein expression
View Patent ↗The present invention relates to the selective inhibition of protein expression of CAG repeat-related disease proteins such as Huntingtin using nucleic acid analogs. Peptide nucleic acids and locked nucleic acids are particularly useful analogs.
1. A method for inhibiting expression of a disease protein encoded by an mRNA having expanded tri-nucleotide repeat region comprising contacting a cell that produces said disease protein with an amount of a nucleic acid analog that targets said repeat region of said mRNA, wherein (i) inhibiting is selective for said disease protein over a normal form of said disease protein, an mRNA for which lacks an expanded tri-nucleotide repeat region, and (ii) inhibiting does not substantially affect production of said mRNA.
2. The method of claim 1 , wherein said repeat region is about 125 repeats or less in size.
3. The method of claim 2 , wherein said disease protein is Huntingtin, ataxin-3, ataxin-1, ataxin-2 or atrophin1.
4. The method of claim 1 , wherein said nucleic acid analog is about 7 to about 30 bases in length.
5. The method of claim 1 , wherein said nucleic acid analog is a peptide-nucleic acid (PNA).
6. The method of claim 5 , wherein said PNA further comprises a cationic peptide.
7. The method of claim 1 , wherein said nucleic acid analog a locked nucleic acid (LNA).
8. The method of claim 7 , wherein said LNA further comprises a cationic peptide.
9. The method of claim 1 , wherein said nucleic acid analog further targets a repeat region junction.
10. The method of claim 1 , wherein said nucleic acid analog lacks bases that recruit RNAseH.
11. A method for inhibiting expression, in a subject, of a disease protein encoded by an mRNA having expanded tri-nucleotide repeat region comprising administering to said subject an amount of a nucleic acid analog that targets said repeat region of said mRNA, wherein (i) inhibiting is selective for said disease protein over a normal form of said disease protein, an mRNA for which lacks an expanded tri-nucleotide repeat region, and (ii) inhibiting does not substantially affect production of said mRNA.
12. The method of claim 11 , wherein said repeat region is about 125 repeats or less in size.
13. The method of claim 12 , wherein said disease protein is Huntingtin, ataxin-3, ataxin-1, ataxin-2 or atrophin1.
14. The method of claim 11 , wherein said nucleic acid analog is about 7 to about 30 bases in length.
15. The method of claim 11 , wherein said nucleic acid analog is a peptide-nucleic acid (PNA).
16. The method of claim 15 , wherein said PNA comprises at least one modified base.
17. The method of claim 16 , wherein said modified base is [bis-o-(aminoethoxy)phenyl]pyrrolocytosine.
18. The method of claim 15 , wherein said PNA further comprises a cationic peptide.
19. The method of claim 11 , wherein said nucleic acid analog a locked nucleic acid (LNA).
20. The method of claim 19 , wherein said LNA further comprises a cationic peptide.
21. The method of claim 11 , wherein said nucleic acid analog further targets a repeat region junction.
22. The method of claim 11 , wherein said nucleic acid analog lacks bases that recruit RNAseH.
23. The method of claim 11 , wherein said nucleic acid analog is administered more than once.
24. The method of claim 23 , wherein said nucleic acid analog is administered at least about once every week.
25. The method of claim 11 , wherein said nucleic acid analog is administered orally, intravenously, intraarterially, intramuscularly or into the CNS.
26. The method of claim 11 , wherein said nucleic acid analog is administered in a lipid formulation.
27. The method of claim 11 , further comprising administering a second therapy to said subject.