US2021108209A1PendingUtilityA1
Products and Methods for Treatment of Familial Amyotrophic Lateral Sclerosis
Assignee: RES INST NATIONWIDE CHILDRENS HOSPITALPriority: Aug 27, 2013Filed: Aug 19, 2020Published: Apr 15, 2021
Est. expiryAug 27, 2033(~7.1 yrs left)· nominal 20-yr term from priority
C12N 2750/14143C12N 9/0089C12N 15/1137C12N 2310/531C12N 15/86C12N 2320/32A61K 31/7105A61P 25/02C12N 2310/14A61K 9/0019C12Y 115/01001C12N 2750/14043A61P 25/28C12N 7/00
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Claims
Abstract
The present invention relates to RNA-based methods for inhibiting the expression of the superoxide dismutase 1 (SOD-1) gene. Recombinant adeno-associated viruses of the invention deliver DNAs encoding RNAs that knock down the expression of SOD-1. The methods have application in the treatment of amyotrophic lateral sclerosis.
Claims
exact text as granted — not AI-modified1 - 3 . (canceled)
4 . A method of delivering a SOD1 shRNA-encoding DNA, to a subject in need thereof, comprising administering to the subject a recombinant adeno-associated virus comprising the SOD1 shRNA-encoding DNA, a sequence selected from the group consisting of:
(SEQ ID NO: 1)
GCATCATCAATTTCGAGCAGAAGGAA,
(SEQ ID NO: 2)
GAAGCATTAAAGGACTGACTGAA,
(SEQ ID NO: 3)
CTGACTGAAGGCCTGCATGGATT,
(SEQ ID NO: 4)
CATGGATTCCATGTTCATGA,
(SEQ ID NO: 5)
GCATGGATTCCATGTTCATGA,
(SEQ ID NO: 6)
GGTCTGGCCTATAAAGTAGTC,
(SEQ ID NO: 7)
GGGCATCATCAATTTCGAGCA,
(SEQ ID NO: 8)
GCATCATCAATTTCGAGCAGA,
(SEQ ID NO: 9)
GCCTGCATGGATTCCATGTTC,
(SEQ ID NO: 10)
GGAGGTCTGGCCTATAAAGTA,
(SEQ ID NO: 11)
GATTCCATGTTCATGAGTTTG,
(SEQ ID NO: 12)
GGAGATAATACAGCAGGCTGT,
(SEQ ID NO: 13)
GCTTTAAAGTACCTGTAGTGA,
(SEQ ID NO: 14)
GCATTAAAGGACTGACTGAAG,
(SEQ ID NO: 16)
TCGAGCAGAAGGAAAGTAA,
(SEQ ID NO: 17)
GCCTGCATGGATTCCATGT,
(SEQ ID NO: 18)
TCACTCTCAGGAGACCATT,
and
(SEQ ID NO: 19)
GCTTTAAAGTACCTGTAGT;
wherein the recombinant adeno-associated virus genome lacks rep and cap genes.
5 - 11 . (canceled)
12 . The method of claim 4 , wherein the subject has amyotrophic lateral sclerosis (ALS).
13 . The method of claim 12 , wherein the ALS is associated with one or more SOD1 mutations.
14 . The method of claim 4 , wherein the adeno-associated virus further comprises an H1 promoter operably linked to the SOD1 shRNA-encoding DNA.
15 . The method of claim 14 , wherein the H1 promoter comprises nucleotides 966 to 1064 of SEQ ID NO:20.
16 . The method of claim 4 , wherein the virus genome is a self-complementary genome.
17 . The method of claim 4 , wherein the recombinant adeno-associated virus is an rAAV2, rAAV9 or rAAVrh74 virus.
18 . The method of claim 17 , wherein the recombinant adeno-associated virus is rAAV9.
19 . The method of claim 4 , wherein the adeno-associated virus further comprises a stuffer sequence.
20 . The method of claim 19 , wherein the stuffer sequence comprises SEQ ID NO: 22.
21 . The method of claim 4 , wherein the SOD1 shRNA-encoding DNA comprises SEQ ID NO: 4.
22 . The method of claim 4 , wherein the SOD1 shRNA-encoding DNA comprises, from 5′ to 3′: a) nucleotides 104-123 of SEQ ID NO: 21; b) a stem loop; and c) nucleotides 133-152 of SEQ ID NO: 21.
23 . The method of claim 4 , wherein recombinant adeno-associated virus is administered by parenteral, intravenous, intrathecal introcerebroventricular, or cisterna magna administration.
24 . The method of claim 23 , wherein the recombinant adeno-associated virus is administered by intrathecal administration.
25 . The method of claim 24 , wherein the intrathecal administration is by lumbar puncture.
26 . A superoxide dismutase 1 (SOD1) shRNA-encoding DNA comprising:
(SEQ ID NO: 1)
GCATCATCAATTTCGAGCAGAAGGAA,
(SEQ ID NO: 2)
GAAGCATTAAAGGACTGACTGAA,
(SEQ ID NO: 3)
CTGACTGAAGGCCTGCATGGATT,
(SEQ ID NO: 4)
CATGGATTCCATGTTCATGA,
(SEQ ID NO: 5)
GCATGGATTCCATGTTCATGA,
(SEQ ID NO: 6)
GGTCTGGCCTATAAAGTAGTC,
(SEQ ID NO: 7)
GGGCATCATCAATTTCGAGCA,
(SEQ ID NO: 8)
GCATCATCAATTTCGAGCAGA,
(SEQ ID NO: 9)
GCCTGCATGGATTCCATGTTC,
(SEQ ID NO: 10)
GGAGGTCTGGCCTATAAAGTA,
(SEQ ID NO: 11)
GATTCCATGTTCATGAGTTTG,
(SEQ ID NO: 12)
GGAGATAATACAGCAGGCTGT,
(SEQ ID NO: 13)
GCTTTAAAGTACCTGTAGTGA,
(SEQ ID NO: 14)
GCATTAAAGGACTGACTGAAG,
(SEQ ID NO: 16)
TCGAGCAGAAGGAAAGTAA,
(SEQ ID NO: 17)
GCCTGCATGGATTCCATGT,
(SEQ ID NO: 18)
TCACTCTCAGGAGACCATT,
or
(SEQ ID NO: 19)
GCTTTAAAGTACCTGTAGT.
27 . A DNA plasmid comprising a recombinant adeno-associated virus genome comprising a superoxide dismutase 1 (SOD1) shRNA-encoding DNA comprising a sequence selected from the group consisting of:
(SEQ ID NO: 1)
GCATCATCAATTTCGAGCAGAAGGAA,
(SEQ ID NO: 2)
GAAGCATTAAAGGACTGACTGAA,
(SEQ ID NO: 3)
CTGACTGAAGGCCTGCATGGATT,
(SEQ ID NO: 4)
CATGGATTCCATGTTCATGA,
(SEQ ID NO: 5)
GCATGGATTCCATGTTCATGA,
(SEQ ID NO: 6)
GGTCTGGCCTATAAAGTAGTC,
(SEQ ID NO: 7)
GGGCATCATCAATTTCGAGCA,
(SEQ ID NO: 8)
GCATCATCAATTTCGAGCAGA,
(SEQ ID NO: 9)
GCCTGCATGGATTCCATGTTC,
(SEQ ID NO: 10)
GGAGGTCTGGCCTATAAAGTA,
(SEQ ID NO: 11)
GATTCCATGTTCATGAGTTTG,
(SEQ ID NO: 12)
GGAGATAATACAGCAGGCTGT,
(SEQ ID NO: 13)
GCTTTAAAGTACCTGTAGTGA,
(SEQ ID NO: 14)
GCATTAAAGGACTGACTGAAG,
(SEQ ID NO: 16)
TCGAGCAGAAGGAAAGTAA,
(SEQ ID NO: 17)
GCCTGCATGGATTCCATGT,
(SEQ ID NO: 18)
TCACTCTCAGGAGACCATT,
and
(SEQ ID NO: 19)
GCTTTAAAGTACCTGTAGT,
wherein the recombinant adeno-associated virus genome lacks rep and cap genes.
28 . A packaging cell comprising the DNA plasmid of claim 27 .Join the waitlist — get patent alerts
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