Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
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.
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.