Compositions and methods of treating amyotrophic lateral sclerosis (ALS)

Patent metadata

Field	Value
Publication number	US-10920227-B2
Application number	US-202016774493-A
Country	US
Kind code	B2
Filing date	Jan 28, 2020
Priority date	Nov 14, 2014
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

The present invention relates to small interfering RNA (siRNA) molecules against the SOD1 gene, adeno-associated viral (AAV) vectors encoding siRNA molecules and methods for treating amyotrophic lateral sclerosis (ALS) using the siRNA molecules and AAV vectors.

First claim

We claim:

1. An adeno-associated virus (AAV) vector genome comprising a nucleic acid sequence positioned between two inverted terminal repeats (ITRs); wherein said nucleic acid sequence encodes a sense strand sequence and an antisense strand sequence of an siRNA duplex; wherein the antisense strand sequence comprises nucleotides 1-17 of SEQ ID NO. 292; and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 123 or nucleotides 1-19 of SEQ ID NO. 124.

2. The AAV vector genome of claim 1 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 292.

3. The AAV vector genome of claim 1 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 293.

4. The AAV vector genome of claim 1 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 292, and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 123.

5. The AAV vector genome of claim 1 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 293, and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 124.

6. The AAV vector genome of claim 1 , wherein the sense strand sequence and the antisense strand sequence are, independently, between 18-22 nucleotides in length.

7. The AAV vector genome of claim 6 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 1 nucleotide.

8. The AAV vector genome of claim 7 , wherein the 3′ overhang is a deoxyribonucleotide.

9. An adeno-associated virus (AAV) particle comprising the AAV vector genome of claim 6 .

10. The AAV particle of claim 9 , comprising an AAVrh10 capsid.

11. A method for inhibiting the expression of SOD1 gene in a cell comprising administering to the cell a composition comprising an AAV particle of claim 9 .

12. The method of claim 11 , wherein the cell is a mammalian motor neuron or astrocyte.

13. A method for treating amyotrophic lateral sclerosis (ALS) in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an AAV particle of claim 9 .

14. The method of claim 13 , wherein the expression of SOD1 gene in a cell of the subject is inhibited or suppressed by about 50% to about 93%.

15. The method of claim 13 , wherein the administration of the composition comprises intraparenchymal spinal administration.

16. An siRNA duplex comprising a sense strand sequence and an antisense strand sequence; wherein the antisense strand sequence comprises nucleotides 1-17 of SEQ ID NO. 292; and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 123 or nucleotides 1-19 of SEQ ID NO. 124.

17. The siRNA duplex of claim 16 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 292.

18. The siRNA duplex of claim 16 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 293.

19. The siRNA duplex of claim 16 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 292, and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 123.

20. The siRNA duplex of claim 19 , wherein the sense strand sequence and the antisense strand sequence are, independently, between 18-22 nucleotides in length.

21. The siRNA duplex of claim 16 , wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 293, and wherein the sense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 124.

22. The siRNA duplex of claim 21 , wherein the sense strand sequence and the antisense strand sequence are, independently, between 18-22 nucleotides in length.

Assignees

• Voyager Therapeutics Inc

Inventors

• Sah Dinah Wen-Yee
• Hou Jinzhao
• Nonnenmacher Mathieu E
• Zhou Pengcheng
• Hossbach Markus
• Deckert Jochen

Classifications

• C12N15/11 Primary

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C12N15/1137 Primary

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C12N15/85

  for animal cells · CPC title