IP Library › Granted Patent US 12,186,369
Granted Patent B2
US 12,186,369 · App. 16/648,922 · Granted Jan 7, 2025

Gene therapy strategy to restore electrical and cardiac function, and cardiac structure, in arrhythmogenic right ventricular cardiomyopathy

Inventors: Farah Sheikh (La Jolla, CA); Jing Zhang (La Jolla, CA)
Assignee: The Regents of the University of California
A61K38/177A61K35/761A61P9/06C12N7/00C12N15/86A61K48/00C12N2710/10343C12N2750/14143
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Quick Facts
Patent No.
US 12,186,369
App. No.
16/648,922
Granted
Jan 7, 2025
Kind
B2
Abstract

Disclosed herein are methods of treating arrhythmogenic right ventricular cardiomyopathy in a subject, comprising administering a gene therapy construct comprising a connexin 43 sequence, wherein as a result of the administration, connexin 43 levels in at least a portion of the heart are increased. Further disclosed are other cardiovascular diseases can be treated with the method.

Claims (12)

1. A method for treating arrhythmogenic right ventricular cardiomyopathy (ARVC) in a subject in need thereof, comprising systemically administering to the subject an adeno-associated virus (AAV) vector encoding a connexin 43 polypeptide sequence operably linked to a promoter that is active in cardiac muscle tissue such that connexin 43 polypeptide levels in at least a portion of the heart of the subject are increased.

2. The method according to claim 1 , wherein the connexin 43 polypeptide sequence comprises a 382 amino acid sequence of SEQ ID NO: 1, or a functional fragment thereof.

3. The method of claim 2 , wherein the sequence encoding the connexin 43 polypeptide is SEQ ID NO: 2.

4. The method of claim 1 , wherein the AAV vector is from the group of an AAV1, AAV2 or an AAV9 serotype.

5. The method according to claim 1 , wherein the promoter is a cardiac-specific promoter.

6. The method according to claim 5 , wherein the promoter is a troponin-T promoter.

7. The method according to claim 1 , wherein the subject is a mammal.

8. The method of claim 7 , wherein the subject is a human.

9. The method according to claim 1 , wherein the effective amount is from about 2×10 11 to about 2×10 14 viral genomes of the AAV vector per kg of body weight of the subject.

10. The method according claim 1 , wherein as a result of the administration, cardiac electrical dysfunction is reduced.

11. The method according to claim 1 , wherein as a result of the administration, cardiac physiologic dysfunction is reduced.

12. The method of according to claim 1 , wherein as a result of the administration, cardiac structural integrity is improved.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 27, 2021
From: SHEIKH, FARAH; ZHANG, JING
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 056374/0927 →
Continuity (2)
Provisional Application 62560989 · Sep 20, 2017
Related Publication 20200215155A1 · Jul 9, 2020
References Cited (66)
US 6309634B1 · Bankiewicz et al. · 2001 [cited by applicant]
US 7317950B2 · Lee · 2008 [cited by applicant]
US 7494644B2 · Lee · 2009 [cited by applicant]
US 7840263B2 · Girouard et al. · 2010 [cited by applicant]
US 10501756B2 · Hamburg-Eppendorf et al. · 2019 [cited by applicant]
US 20050260623A1 · Trosko et al. · 2005 [cited by applicant]
US 20060088503A1 · Sharma et al. · 2006 [cited by applicant]
US 20080019953A1 · Lee · 2008 [cited by applicant]
US 20090054828A1 · Stolen et al. · 2009 [cited by applicant]
US 20100179609A1 · Girouard et al. · 2010 [cited by applicant]
US 20110077702A1 · Boink · 2011 [cited by examiner]
US 20110129449A1 · Cohen et al. · 2011 [cited by applicant]
US 20110256112A2 · Cohen · 2011 [cited by examiner]
CN 1703257A · 2005 [cited by applicant]
CN 106596972A · 2017 [cited by applicant]
JP 2005527482A · 2005 [cited by applicant]
JP 2008506467A · 2008 [cited by applicant]
JP 2008515997A · 2008 [cited by applicant]
WO 19988002150A1 · 1998 [cited by applicant]
WO 2002019966A2 · 2002 [cited by applicant]
WO 2003039344A2 · 2003 [cited by applicant]
WO 2006019856A1 · 2006 [cited by applicant]
WO 2006044589A2 · 2006 [cited by applicant]
WO WO2006134494A2 · 2006 [cited by examiner]
WO 2009025812A2 · 2009 [cited by applicant]
WO 2017152149A1 · 2017 [cited by applicant]
WO 2017180896A1 · 2017 [cited by applicant]
WO 2021025725A1 · 2021 [cited by applicant]
Lyon et al., “Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model,” Human Molecular Genetics, vol. 23, No. 5: 1134-1150 (Year: 2014). [cited by examiner]
Fishman et al., “The Human Connexin Gene Family of Gap Junction Proteins: Distinct Chromosomal Locations but Similar Structures,” Genomics 10: 250-256 (Year: 1991). [cited by examiner]
Bikou et al. “Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model,” Cardiovasc Res 92:218-225, 2011. [cited by applicant]
Fernandes et al. “Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias,” J Cell Mol Med 13:3703-3712, 2009. [cited by applicant]
Fidler et al. “Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophillin-2 mutations,” J Cell Mol Med 13:4219-4228, 2009. [cited by applicant]
Kurotobi et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 3:39-45, 2010. [cited by applicant]
Wolfram and Donohue “Gene therapy to treat cardiovascular disease,” J Am Heart Assoc 2013;2:e000119 doi: 10.1161/JAHA.113.000119. [cited by applicant]
Chelko et al. “Central role for GSK3b in the pathogenesis of arrhythmogenic cardiomyopathy,” JCI Insight. 2016; 1(5):e85923. doi:10.1172/jci.insight.85923. [cited by applicant]
Lyon et al. “Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model,” Hum Mol Genet 23:1134-1150, 2014. [cited by applicant]
Greener et al. “Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction,” 60:1103-1110, 2012. [cited by applicant]
Garashi et al. “Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation,” Circulation 125:216-225, 2012. [cited by applicant]
Asokan and Samulski “An Emerging Adeno-Associated Viral Vector Pipeline for Cardiac Gene Therapy,” Hum Gene Ther. 24(11): 906-913, 2013. [cited by applicant]
Phillips et al. “Systemic Gene Transfer to Skeletal Muscle Using Reengineered AAV Vectors,” Methods Mol Biol. 709:141-51, 2011. [cited by applicant]
Pacak and Byrne “AAV Vectors for Cardiac Gene Transfer: Experimental Tools and Clinical Opportunities,” Mol. Ther. 19(9):1582-1590, 2011. [cited by applicant]
Ozawa “Gene Therapy Using AAV Vectors,” Drug Delivery System, 2007, vol. 22-6, pp. 643-650. [cited by applicant]
“Arrhythmogenic right ventricular cardiomyopathy,” Jpn. J. Electrocardiology, 2014, vol. 43, No. 3, pp. 245-263. [cited by applicant]
Wu and Lu “Loss of anti-arrhythmic effect of vagal nerve stimulation on ischemia-induced ventricular tachyarrhythmia in aged rats,” Tohoku Journal of Experimental Medicine, 2011, vol. 223, No. 1, pp. 27-33. [cited by applicant]
Chinese Office Action dated Aug. 22, 2023 for Chinese Application No. 201880061433.4, 6 pages (with unofficial translation). [cited by applicant]
Chen, Guiying et al., MG132 proteasome inhibitor upregulates the expression of connexin 43 in rats with adriamycin-induced heart failure, Molecular Medicine Reports 12: 7595-7602 (Year: 2015). [cited by applicant]
JPO, Notice of Decision to Grant dated Nov. 28, 2023 for Application No. 2020-516572, 3 pages. [cited by applicant]
Israel Patent Office, First Office Action dated Nov. 12, 2023 for Application No. 273448, 4 pages. [cited by applicant]
USPTO, Non-Final Office Action dated Mar. 30, 2023 for U.S. Appl. No. 16/862,326, 18 pages. [cited by applicant]
USPTO, Notice of Allowance dated Jan. 4, 2024 for U.S. Appl. No. 16/862,326, 12 pages. [cited by applicant]
Zhang et al., “Silencing of desmoplakin decreases connexin43/Nav1.5 expression and sodium current in HL-1 cardiomyocytes,” Molecular Medicine Reports 8: 780-786 (Year: 2013). [cited by applicant]
USPTO, Notice of Allowance for U.S. Appl. No. 16/862,326, mailed on Apr. 10, 2024, 8 pages. [cited by applicant]
EPO, Extended European Search Report for Application No. 23210043.8, mailed May 13, 2024, 8 pages. [cited by applicant]
Asokan et al., “Reengineering a receptor footprint of adeno-associated virus enables selective and system gene transfer to muscle,” Nat Biotechnol. (1):79-82, 2010. [cited by applicant]
EPO, Extended European Search Report for Application No. 188858620.0, Mail Date: May 25, 2021, 7 pages. [cited by applicant]
IP Office China, First Office Action with Search Report for Application No. 201880061433.4, Mail Date: May 25, 2021. [cited by applicant]
IP Office China, Second Office Action with Search Report for Application No. 201880061433.4, Mail Date: Mar. 10, 2023. [cited by applicant]
IP Office Japan, Notice of Reasons for Refusal for Application No. 2020-516572, Mail Date: Jul. 26, 2022. [cited by applicant]
IP Office Japan, Notice of Reasons for Refusal for Application No. 2020-516572, Mail Date: Mar. 7, 2023. [cited by applicant]
ISA/US, International Search Report and Written Opinion for Application No. PCT/US18/52057, Mail Date: Feb. 14, 2019, 14 pages. [cited by applicant]
Rickelt, “Plakophilin-2: a cell-cell adhesion plaque molecule of selective and fundamental importance in cardiac functions and tumor cell growth,” Cell Tissue Res 348:281-294 (Year: 2012). [cited by applicant]
Smyth et al., “Autoregulation of connexin43 gap junction formation by internally translated isoforms,” Cell Rep. 5(3):611-8, 2013. [cited by applicant]
USPTO, Notice of Allowance for U.S. Appl. No. 16/862,326, mailed on Jul. 26, 2024, 13 pages. [cited by applicant]
IP Office Australia, Exam Report No. 1 for Australian Application No. 2018335401, Mail Date: Jul. 31, 2024, 5 pages. [cited by applicant]
CIPO, Examiner's Report for Application No. 3,076,227, mailed Sep. 19, 2024, 2024, 5 pages. [cited by applicant]