RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
View Patent ↗The present invention concerns methods and reagents useful in modulating BACE gene expression in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Specifically, the invention relates to small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against beta-secretase (BACE), amyloid precursor protein (APP), pin-1, presenillin 1 (PS-1) and/or presenillin 2 (PS-2) gene expression and/or activity. The small nucleic acid molecules are useful in the treatment of Alzheimer's disease and any other condition that responds to modulation of BACE, APP, pin-1, PS-1 and/or PS-2 expression or activity.
1. A chemically modified nucleic acid molecule, wherein:
(a) the nucleic acid molecule comprises a sense strand having SEQ ID NO:657 and a separate antisense strand having SEQ ID NO:661; and
(b) each strand of the nucleic acid molecule is independently 18 to 27 nucleotides in length.
2. The nucleic acid molecule of claim 1 , wherein one or more nucleotides comprise a 2′-sugar modification.
3. The nucleic acid molecule of claim 2 , wherein the 2′-sugar modification is selected from the group consisting of 2′-deoxy-2′-fluoro, 2′-O-methyl, and 2′-deoxy.
4. The nucleic acid of claim 3 , wherein the 2′-deoxy-2′-fluoro sugar modification is a pyrimidine modification.
5. The nucleic acid of claim 3 , wherein the 2′-deoxy sugar modification is a pyrimidine modification.
6. The nucleic acid of claim 3 , wherein the 2′-O-methyl sugar modification is a pyrimidine modification.
7. The nucleic acid molecule of claim 4 , wherein said pyrimidine modification is in the sense strand, the antisense strand, or both the sense strand and antisense strand.
8. The nucleic acid molecule of claim 6 , wherein said pyrimidine modification is in the sense strand, the antisense strand, or both the sense strand and antisense strand.
9. The nucleic acid molecule of claim 3 , wherein the 2 ′-deoxy sugar modification is a purine modification.
10. The nucleic acid molecule of claim 3 , wherein the 2′-O-methyl sugar modification is a purine modification.
11. The nucleic acid molecule of claim 9 , wherein the purine modification is in the sense strand.
12. The nucleic acid molecule of claim 10 , wherein the purine modification is in the antisense strand.
13. The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule comprises ribonucleotides.
14. The nucleic acid molecule of claim 1 , wherein the sense strand includes a terminal cap moiety at the 5′-end, the 3′-end, or both of the 5′- and 3′- ends.
15. The nucleic acid molecule of claim 14 , wherein the terminal cap moiety is an inverted deoxy abasic moiety.
16. The nucleic acid molecule of claim 1 , wherein said nucleic acid molecule includes one or more phosphorothioate internucleotide linkages.
17. The nucleic acid molecule of claim 16 , wherein one of the phosphorothioate internucleotide linkages is at the 3′-end of the antisense strand.
18. The nucleic acid molecule of claim 1 , wherein the 5′-end of the antisense strand includes a terminal phosphate group.
19. A composition comprising the nucleic acid molecule of claim 1 , in a pharmaceutically acceptable carrier or diluent.