Connexin-43 Restoration Alleviates Desmosomal Arrhythmogenic Cardiomyopathy
Jing Zhang1, Fabian Zanella1, Matthew W Ellis1
1Department of Medicine (J.Z., F.Z., M.W.E., W.H.B., E.J.G.-L., T.-M.W., K.F., C.D., R.C.L., V.M., Y.G., K.L.P., F.S.), University of California San Diego, La Jolla.
Circulation. Heart Failure
|January 26, 2026
Summary
Gene therapy restoring connexin-43 (Cx43) effectively treated arrhythmogenic cardiomyopathy (ACM) in preclinical models. This mutation-agnostic approach offers a potential treatment for diverse ACM populations by targeting Cx43
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Medicine
Background:
- Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease caused by desmosomal gene mutations.
- Reduced connexin-43 (Cx43) expression is a common molecular defect in ACM, leading to arrhythmias.
- Current therapies for ACM are limited, especially for genetically diverse patient groups.
Purpose of the Study:
- To investigate if restoring Cx43 expression can serve as a mutation-agnostic therapeutic strategy for ACM.
- To evaluate the efficacy of adeno-associated-viral-mediated Cx43 gene therapy in preclinical ACM models.
Main Methods:
- Adeno-associated-viral-mediated gene therapy was used to restore Cx43 in mouse and human stem cell models of ACM.
- Models included mutations in desmoplakin (Dsp), plakophilin-2 (PKP2), and desmoglein-2 (DSG2).
Main Results:
- AAV-Cx43 gene therapy improved cardiac function, reduced arrhythmias, and prolonged survival in desmosomal ACM mouse models.
- Restoration of Cx43 alleviated physiological deficits in human ACM cardiomyocytes with PKP2 and DSG2 mutations.
- Mechanistically, Cx43 improved desmosomal protein stability and cell-cell coupling.
Conclusions:
- Cx43 gene therapy is sufficient to ameliorate ACM deficits across different genetic backgrounds.
- Cx43's noncanonical functions in mechanical modulation and desmosome reassembly present a therapeutic target for diverse ACM populations.
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