IP Library › Granted Patent US 12,404,522
Granted Patent B2
US 12,404,522 · App. 16/962,877 · Granted Sep 2, 2025

Disrupting the LINC complex for treating laminopathy

Inventors: Colin Lawson Stewart (Singapore, SG); Jinfen Chai (Singapore, SG); Yin Loon Lee (Singapore, SG); Brian Edmund Burke (Singapore, SG)
Assignee: Agency for Science, Technology and Research
C12N15/86A61P9/00C12N7/00G01N33/502C12N2750/14143
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Quick Facts
Patent No.
US 12,404,522
App. No.
16/962,877
Granted
Sep 2, 2025
Kind
B2
Abstract

The present invention relates to use of expression vectors and other compounds in methods to disrupt the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, uncoupling the nucleus from its linkage to the cytoskeleton, resulting in amelioration of diseases caused by one or more Lmna mutations, so-called laminopathies. More particularly, the invention relates to the expression of dominant negative SUN domain protein and/or dominant negative KASH domain protein to disrupt, for example, the LINC complex in cardiomyocytes for suppressing disease progression in dilated cardiomyopathy (DCM).

Claims (13)

1. A method of treating a laminopathy in a subject in need thereof, wherein the laminopathy is a disease caused by a mutation in the Lamin A (LMNA) gene, the method comprising administering to the subject an effective amount of an adeno-associated virus (AAV) expression vector operably linked to a transgene; wherein the transgene comprises a nucleic acid sequence encoding a dominant negative Sun domain containing protein; wherein the AAV expression vector comprises a cardiac-or cardiomyocyte-specific promoter; wherein the AAV expression vector is administered intravascularly, wherein expression of the dominant negative Sun domain containing protein disrupts the protein-protein interactions of the Linker of Nucleoskeleton and Cyotoskeleton (LINC) complex, which uncouples the nucleus from its linkage to the cytoskeleton, resulting in treatment of the laminopathy.

2. The method according to claim 1 , wherein the protein-protein interaction is between a Sad Ip UNC-84 (SUN) domain and a Klarsicht, Anc-1 and a Syne Homology (KASH) domain of the LINC complex.

3. The method according to claim 1 , wherein the nucleic acid further comprises a lumenal domain of a Sun domain containing protein, an N-terminal signal sequence, a signal peptidase cleavage site, and a C-terminal targeting peptide sequence preventing secretion of the SUN domain-containing protein, wherein the lumenal domain comprises a coiled coil domain and a Sun domain.

4. The method according to claim 3 , wherein the SUN domain-containing protein is SUN1 or SUN2.

5. The method according to claim 3 , wherein the C-terminal targeting peptide sequence is a KDEL sequence.

6. The method according to claim 1 , wherein the AAV expression vector is a cardiac or cardiomyocyte-specific expression vector.

7. The method according to claim 6 , wherein in the AAV expression vector is selected from the group consisting of: AAV9, AAV1, AAV6, AAV8, AAV2i8, and AAV9.45.

8. The method according to claim 1 , wherein the cardiac-or cardiomyocyte-specific promoter is selected from the group consisting of: a cardiac troponin T promoter (cTnT), a a-myosin heavy chain (a-MHC) promoter and a myosin light chain (MLC2v) promoter.

9. The method according to claim 1 , wherein laminopathy is selected from the group consisting of: Acrogeria, Gottron Type; Arrhythmogenic cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy; Arthropathy syndrome, autosomal recessive; Atrial fibrillation; Atypical progeroid syndrome; Atypical Werner syndrome; Autosomal dominant spinal muscular dystrophy; Axonal neuropathy; muscular dystrophy [; cardiac disease or cardiomyopathy; Axonal neuropathy, muscular dystrophy, cardiac disease, leuconychia; Cardiac arrhythmia; Cardiac conduction defect; Cardiomyopathy with advanced atrioventricular block and arrhythmia; Charcot-Marie-Tooth disease type 2; Congenital fiber type disproportion; Congenital muscular dystrophy; Diabetes Mellitus, Non-Insulin-Dependent (NIDDM); Dilated cardiomyopathy; Distal acroosteolysis, poikiloderma and joint stiffness (DAPJ); Distal motor neuropathy; Dropped Head Syndrome; Emery-Dreifuss muscular dystrophy, autosomal dominant; Familial partial lipodystrophy (Dunnigan Type); Familial partial lipodystrophy, Kobberling; Generalized lipoatrophy syndrome; Hallerman-Streiff syndrome; Heart-hand syndrome, Slovenian Type; Hutchinson-Gilford progeria syndrome; Lamin-related rigid spine muscular dystrophy; Limb-girdle muscular dystrophy type 1B; Muscular dystrophy; Lone atrial fibrillation; Mandibuloacral dysplasia with type A lipodystrophy; Metabolic Syndrome; Muscular dystrophy and lipodystrophy; Progeroid syndrome, neonatal;-Restrictive dermopathy; Spinal muscular atrophy with cardiac involvement; Type A insulin resistance syndrome; cardiomyopathy associated with Emery-Dreifuss muscular dystrophy (autosomal dominant); cardiomyopathy associated with Emery-Dreifuss muscular dystrophy (autosomal recessive); cardiomyopathy associated with Limb-girdle muscular dystrophy type 1B; cardiomyopathy associated with congenital muscular dystrophy; and a premature aging syndrome; cardiomyopathy associated with Atypical Werner syndrome; and cardiomyopathy associated with Hutchinson-Gilford progeria syndrome.

10. The method of claim 9 , wherein the cardiac disease or cardiomyopathy is selected from the group consisting of Arrhythmogenic cardiomyopathy, dilated cardiomyopathy 1 Az, and dilated cardiomyopathy with conduction system defects.

11. The method of claim 9 , wherein the muscular dystrophy is selected from the group consisting of Autosomal dominant spinal muscular dystrophy; Congenital muscular dystrophy; Emery-Dreifuss muscular dystrophy, autosomal dominant; Lamin-related rigid spine muscular dystrophy; Limb-girdle muscular dystrophy type 1B; and Spinal muscular atrophy with cardiac involvement.

12. The method of claim 9 , wherein the cardiac disease or cardiomyopathy is selected from the group consisting of Cardiac arrhythmia; Atrial fibrillation; Cardiac conduction defect; Lone atrial fibrillation; Sudden cardiac death; cardiomyopathy associated with Emery-Dreifuss muscular dystrophy; Cardiac conduction defect; cardiomyopathy associated with Limb-girdle muscular dystrophy type 1B; cardiomyopathy associated with congenital muscular dystrophy; cardiomyopathy associated with Atypical Werner syndrome; and cardiomyopathy associated with Hutchinson-Gilford progeria syndrome.

13. The method of claim 9 , wherein the Progeroid syndrome is selected from the group consisting of Progeroid syndrome, neonatal; Acrogeria, Groton Type; Atypical progeroid syndrome; Atypical Werner syndrome; and Hutchinson-Gilford progeria syndrome.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2020
From: STEWART, COLIN LAWSON; CHAI, JINFEN; LEE, YIN LOON; BURKE, BRIAN EDMUND
To: AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH
Reel/Frame 054527/0712 →
Priority Claims (1)
SG 10201800530Q · Jan 19, 2018 · national
Continuity (2)
Continuation In Part PCTSG1950033 · Jan 18, 2019
Related Publication 20200347408A1 · Nov 5, 2020
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