IP Library Granted Patent US 12,275,941
Granted Patent B2
US 12,275,941 · App. 17/231,963 · Granted Apr 15, 2025

Products and methods for inhibition of expression of dynamin-1 variants

Inventors: Scott Quenton Harper (Powell, OH); Wayne N. Frankel (Katonah, NY)
Assignees: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL; THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
C12N15/1138A61K31/713C12N15/86C12N2310/14C12N2750/14143
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Quick Facts
Patent No.
US 12,275,941
App. No.
17/231,963
Granted
Apr 15, 2025
Kind
B2
Abstract

RNA interference-based methods and products for inhibiting the expression of pathogenic dynamin-1 variants are provided. Delivery vehicles such as recombinant adeno-associated viruses deliver DNAs encoding RNAs that inhibit the expression of the dynamin-1 variants. The methods treat, for example, developmental and epileptic encephalopathies.

Claims (36)

1. A nucleic acid comprising

(a) a polynucleotide sequence comprising at least 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17;

(b) a polynucleotide sequence encoding a DNM1 artificial inhibitory RNA comprising the artificial inhibitory RNA polynucleotide sequence set forth in any one of SEQ ID NOs: 18-34; or

(c) a polynucleotide sequence encoding a mature DNM1 antisense guide strand comprising the polynucleotide sequence set forth in any one of SEQ ID NO: 35-51.

2. The nucleic acid of claim 1 , wherein

(a) the polynucleotide sequence comprises at least 85% identity to the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17.

3. The nucleic acid of claim 1 , wherein

(a) the polynucleotide sequence comprises at least 90% identity to the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17.

4. The nucleic acid of claim 1 , wherein

(a) the polynucleotide sequence comprises at least 95% identity to the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17.

5. The nucleic acid of claim 1 , wherein

(a) the polynucleotide sequence comprises at least 98% identity to the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17.

6. The nucleic acid of claim 1 , wherein

(a) the polynucleotide sequence comprises the dynamin-1 (DNM1) artificial inhibitory RNA-encoding polynucleotide sequence set forth in any one of SEQ ID NOs: 1-17.

7. A viral vector comprising the nucleic acid of claim 1 or a combination of any one or more thereof.

8. The viral vector of claim 7 , wherein the viral vector is an adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, herpes simplex virus, vaccinia virus, or a synthetic virus.

9. The viral vector of claim 8 , wherein the viral vector is an AAV.

10. The viral vector of claim 9 , wherein the AAV lacks rep and cap genes.

11. The viral vector of claim 10 , wherein the AAV is a recombinant AAV (rAAV) or a self-complementary recombinant AAV (scAAV).

12. The viral vector of claim 9 , wherein the AAV has a capsid serotype of: AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12, AAV-13, AAV-anc80, or AAV rh.74.

13. The viral vector of claim 12 , wherein the AAV has a capsid serotype of AAV-9.

14. The viral vector of claim 9 , wherein the AAV is a pseudotyped AAV.

15. The viral vector of claim 14 , wherein the AAV is AAV2/8 or AAV2/9.

16. The viral vector of claim 7 , wherein expression of the nucleic acid encoding the DNM1 artificial inhibitory RNA is under the control of a U6 promoter.

17. A composition comprising the nucleic acid of claim 1 and a pharmaceutically acceptable carrier.

18. The composition of claim 17 , wherein expression of the nucleic acid encoding the DNM1 artificial inhibitory RNA is under the control of a U6 promoter.

19. A composition comprising the nucleic acid of claim 2 and a pharmaceutically acceptable carrier.

20. A composition comprising the nucleic acid of claim 3 and a pharmaceutically acceptable carrier.

21. A composition comprising the nucleic acid of claim 4 and a pharmaceutically acceptable carrier.

22. A composition comprising the nucleic acid of claim 5 and a pharmaceutically acceptable carrier.

23. A composition comprising the nucleic acid of claim 6 and a pharmaceutically acceptable carrier.

24. A composition comprising the viral vector of claim 7 and a pharmaceutically acceptable carrier.

25. A method of delivery to a neuron with a dynamin-1 (DNM1) gene, the method comprising administering to a subject with the neuron:

(a) the nucleic acid of claim 1 ;

(b) the vector of claim 7 ; or

(c) the composition of claim 17 .

Assignments (3)
CONFIRMATORY LICENSE Recorded Nov 10, 2023
From: CHILDREN'S HOSPITAL COLUMBUS
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065548/0081 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 16, 2022
From: HARPER, SCOTT QUENTON
To: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL
Reel/Frame 059281/0928 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 16, 2022
From: FRANKEL, WAYNE N.
To: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
Reel/Frame 059282/0029 →
Continuity (1)
Related Publication 20220333115A1 · Oct 20, 2022
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