IP Library › Granted Patent US 12,357,707
Granted Patent B2
US 12,357,707 · App. 17/433,927 · Granted Jul 15, 2025

Compositions and methods for treating laminopathies

Inventors: Sirika Wood (South San Francisco, CA); Kartik Ramamoorthi (South San Francisco, CA); Stephanie Tagliatela (South San Francisco, CA); Anne Tanenhaus (South San Francisco, CA)
Assignee: Encoded Therapeutics, Inc.
A61K48/0058C07K14/78C12N15/86C12N2750/14143C12N2830/008
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Quick Facts
Patent No.
US 12,357,707
App. No.
17/433,927
Granted
Jul 15, 2025
Kind
B2
Abstract

The present disclosure provides compositions and methods for treating, preventing, or inhibiting laminopathies. In one aspect, the disclosure provides nucleic acid constructs and/or vectors comprising a nucleotide sequence encoding lamin A and/or lamin C.

Claims (29)

1. A nucleic acid construct comprising a nucleotide sequence encoding a lamin A polypeptide and a lamin C polypeptide, wherein said construct comprises introns 8-11 of the wildtype human LMNA gene and lacks introns 1-7 of the wildtype-human LMNA gene, wherein the lamin A polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 21, and wherein said lamin C polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 13.

2. The nucleic acid construct of claim 1 , wherein intron 8 comprises a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 77.

3. The nucleic acid construct of claim 1 , wherein intron 11 comprises a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 80.

4. The nucleic acid construct of claim 1 , wherein the nucleic acid construct further comprises a regulatory element and wherein the regulatory element has less than or equal to 800 base pairs (bp), 700 bp, 600 bp, 500 bp, 400 bp, 300 bp, 250 bp, 200 bp, 150 bp, 140 bp, 130 bp, 120 bp, 110 bp, 100 bp, 70 bp, or 50 bp.

5. The nucleic acid construct of claim 1 , wherein the regulatory element comprises any one of or a combination of: any one of SEQ ID NOs: 30-58, SEQ ID NO: 102, a cytomegalovirus (CMV) promoter, a chicken β-actin (CBA) promoter, a CMV enhancer used upstream of a CBA promoter, a super core promoter (SCP) promoter, a SerpE TTR promoter, a Protol promoter, a minimal CMV (minCMV) promoter, a University College London hybrid liver-specific promoter (UCL-HLP) promoter, a CMV enhancer (CMVe), a CMV early enhancer/CBA (CAG) promoter, a Myh6 promoter, a Desmin promoter, a cardiac troponin T (cTNT) promoter, an alpha-myosin heavy chain (a-MHC) promoter, a myosin light chain 2 (MLC-2) promoter, and an EF1α short (EFS) promoter.

6. The nucleic acid construct of claim 5 , wherein the regulatory element is cell-type selective.

7. The nucleic acid construct of claim 6 , wherein the regulatory element is selectively expressed in cardiomyocytes.

8. The nucleic acid construct of claim 7 , wherein the regulatory element is any one of or combination of: the Myh6 promoter, the Desmin promoter, the cTNT promoter, the α-MHC promoter, or the MLC-2 promoter.

9. The nucleic acid construct of claim 6 , wherein the regulatory element is the cTNT promoter.

10. The nucleic acid construct of claim 9 , wherein the cTNT promoter comprises SEQ ID NO: 101.

11. The nucleic acid construct of claim 1 , wherein the nucleic acid construct comprises a nucleotide sequence that is at least 95% identical to the nucleotide sequence of SEQ ID NO: 3 or SEQ ID NO: 8.

12. The nucleic acid construct of claim 1 , wherein the lamin A polypeptide comprises SEQ ID NO: 12 or SEQ ID NO: 21 and the lamin C polypeptide comprises SEQ ID NO: 13.

13. The nucleic acid construct of claim 1 , wherein the nucleic acid construct comprises SEQ ID NO: 3 or SEQ ID NO: 8.

14. The nucleic acid construct of claim 1 , wherein the nucleotide sequence further comprises a polyadenylation signal.

15. A viral vector comprising the nucleic acid construct of claim 1 .

16. The viral vector of claim 15 , wherein the viral vector is an adeno-associated virus (AAV) vector.

17. The viral vector of claim 16 , wherein the AAV vector is AAV1, AAV2, AAV5, AAV6, AAV8, AAV9, scAAV1, scAAV2, scAAV5, scAAV6, scAAV8, or scAAV9.

18. The viral vector of claim 16 , wherein the nucleotide sequence further comprises a 5′ AAV inverted terminal repeat (ITR) sequence and a 3′ AAV ITR sequence.

19. A viral particle comprising the viral vector of claim 15 .

20. The viral particle of claim 19 , wherein the viral particle comprises capsid proteins of an AAV.

21. The viral particle of claim 20 , wherein the AAV is an AAV6 or AAV9.

22. A host cell comprising one of the following: the nucleic acid construct of claim 1 , or the viral vector of claim 15, 16, 17 or 18 , or the viral particle of claim 19, 20 or 21 .

23. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, and one of the following: the nucleic acid construct of claim 1 , or the viral vector of claim 15, 16, 17 or 18 , or the viral particle of claim 19, 20 or 21 .

24. A method for treating a laminopathy in a subject comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 23 to a subject in need thereof.

25. The method of claim 24 , wherein the laminopathy is any one or more of: Charcot-Marie-Tooth disease, Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, Hutchinson-Gilford progeria syndrome, limb-girdle muscular dystrophy, LMNA-related congenital muscular dystrophy, mandibuloacral dysplasia, arrhythmogenic right ventricular cardiomyopathy, familial atrial fibrillation, left ventricular noncompaction, or dilated cardiomyopathy.

26. The method of claim 24 , wherein said pharmaceutical composition is administered intramyocardially, intravenously, intramuscularly, intrathecally, subcutaneously, systemically, or locally into the myocardium.

27. A method for expressing a lamin A polypeptide and a lamin C polypeptide in a subject comprising administering to said subject a therapeutically effective amount of one of the following: the nucleic acid construct of claim 1 , or the viral vector of claim 15, 16, 17 or 18 , or the viral particle of claim 19, 20 or 21 .

28. A method for increasing expression of a functional lamin A polypeptide and a functional lamin C polypeptide in a subject comprising administering to said subject a therapeutically effective amount of one of the following: the nucleic acid construct of claim 1 , or the viral vector of claim 15, 16, 17 or 18 , or the viral particle of claim 19, 20 or 21 .

29. The method of claim 28 , wherein the subject is suffering from a laminopathy.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2022
From: WOOD, SIRIKA; RAMAMOORTHI, KARTIK; TAGLIATELA, STEPHANIE; TANENHAUS, ANNE
To: ENCODED THERAPEUTICS, INC.
Reel/Frame 059602/0933 →
Continuity (2)
Provisional Application 62812021 · Feb 28, 2019
Related Publication 20220193264A1 · Jun 23, 2022
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