Compositions and methods of treating amyotrophic lateral sclerosis (ALS)

Patent metadata

Field	Value
Publication number	US-10597660-B2
Application number	US-201515526690-A
Country	US
Kind code	B2
Filing date	Nov 13, 2015
Priority date	Nov 14, 2014
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

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 viral (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 sense strand sequence comprises nucleotides 1-18 of SEQ ID NO. 51; and wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 220.

2. The AAV vector genome of claim 1 , wherein the sense strand sequence and the antisense strand sequence are, independently, 22 nucleotides or less in length.

3. The AAV vector genome of claim 2 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 1 nucleotide.

4. The AAV vector genome of claim 2 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 2 nucleotides.

5. An AAV particle comprising the AAV vector genome of claim 2 .

6. A method for inhibiting the expression of SOD1 gene in a cell comprising administering to the cell a composition comprising an AAV vector genome of claim 2 .

7. The method of claim 6 , wherein the cell is a mammalian cell.

8. The method of claim 7 , wherein the mammalian cell is a motor neuron.

9. The method of claim 7 , wherein the mammalian cell is an astrocyte.

10. A method for treating amyotrophic lateral sclerosis (ALS) caused by SOD1 mutation in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising the AAV particle of claim 5 .

11. The method of claim 10 , wherein the expression of SOD1 mRNA is inhibited or suppressed by up to 93%.

12. The method of claim 10 , wherein the expression of SOD1 mRNA is inhibited or suppressed by about 20% to about 93%.

13. The method of claim 10 , wherein the expression of SOD1 mRNA is inhibited or suppressed by about 50% to about 93%.

14. The method of claim 10 , wherein the ALS is familial ALS with an identified SOD1 gene mutation.

15. The method of claim 10 , wherein the ALS is sporadic ALS caused by SOD1 mutation.

16. The method of claim 10 , wherein the SOD1 gene embraces a mutation that causes a gain of function effect inside the cell.

17. The method of claim 16 , wherein the administration of the composition comprises intraparenchymal spinal administration.

18. The method of claim 10 , wherein the administration of the composition comprises intraparenchymal spinal administration.

19. The AAV vector genome of claim 2 , wherein the sense strand sequence and the antisense strand sequence are, independently, 20 nucleotides in length.

20. The AAV vector genome of claim 2 , wherein the sense strand sequence and the antisense strand sequence are, independently, 21 nucleotides in length.

21. The AAV vector genome of claim 2 , wherein the sense strand sequence and the antisense strand sequence are, independently, 22 nucleotides in length.

22. An siRNA duplex comprising a sense strand sequence and an antisense strand sequence; wherein the sense strand sequence comprises nucleotides 1-18 of SEQ ID NO. 51; and wherein the antisense strand sequence comprises nucleotides 1-19 of SEQ ID NO. 220.

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

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

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

26. The siRNA duplex of claim 22 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 1 nucleotide.

27. The siRNA duplex of claim 22 , wherein at least one of the sense strand sequence and the antisense strand sequence comprise a 3′ overhang of at least 2 nucleotides.

Assignees

• Voyager Therapeutics Inc

Inventors

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

Classifications

• C12N15/85

  for animal cells · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61P43/00

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

• C12N2330/51

  Specially adapted vectors · CPC title

• C12Y115/01001

  Superoxide dismutase (1.15.1.1) · CPC title