Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.

Summary

Using transgenic and AAV-mediated gene delivery models, restoring wild-type TMEM43 counteracted the dominant S358L mutation in ARVC5 mice: delaying disease onset, improving contraction, reducing ECG abnormalities and fibrosis, and prolonging survival. A single systemic AAV dose carrying WT‑TMEM43 prevented ventricular dysfunction and ECG abnormalities induced by mutant TMEM43.

Key Findings

• Double transgenic overexpression of WT plus S358L TMEM43 delayed ARVC5 onset, improved contraction, reduced ECG abnormalities and myocardial fibrosis, and increased survival versus S358L alone.
• Systemic AAV delivery of codon-optimized WT‑TMEM43 prevented ventricular dysfunction and ECG abnormalities induced by mutant TMEM43.
• Cardiomyocyte death and fibrosis were reduced by WT TMEM43 overexpression, indicating target engagement and disease modification.

Clinical Implications

Although preclinical, the data support developing AAV‑mediated TMEM43 augmentation for TMEM43 p.S358L carriers, with implications for early intervention in genotype‑positive individuals and trial design (dose, timing, endpoints).

Limitations

• Preclinical mouse data; human safety, dosing, and long‑term durability remain unknown
• Potential off‑target effects and immune responses to AAV not fully characterized

Future Directions

IND‑enabling studies for AAV‑TMEM43 (toxicology, biodistribution, immunogenicity), large‑animal validation, and early‑phase trials in TMEM43 p.S358L carriers with biomarkers and imaging endpoints.