Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2-Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy.
Summary
Using modified mRNA targeting desmocollin‑2 deficiency, the authors restored desmosomal function and improved cardiac performance in mouse models of ARVC, bridged by human genetic discovery. This provides first-in-class preclinical evidence that mRNA replacement can treat inherited cardiomyopathy by correcting structural protein deficits.
Key Findings
- Genetic discovery of a novel DSC2 (desmocollin‑2) variant linked to ARVC and functional validation in models.
- Modified mRNA delivery restored desmosomal protein expression and improved right ventricular function in Dsc2‑deficient mice.
- Therapeutic mRNA replacement mitigated arrhythmogenic substrate and structural dysplasia, demonstrating disease-modifying potential.
Clinical Implications
While preclinical, this work supports clinical development of modified mRNA replacement for ARVC and potentially other desmosomal cardiomyopathies. It suggests a feasible delivery/efficacy path to correct structural protein deficits without permanent genome alteration.
Why It Matters
Introduces a translational RNA therapy paradigm for desmosomal cardiomyopathy with robust functional rescue in vivo. It opens a therapeutic class beyond gene editing and small molecules for structural cardiomyopathies.
Limitations
- Preclinical mouse data; human safety, dosing, and delivery need evaluation
- Durability of mRNA therapy and immune responses were not fully established
Future Directions
Optimize cardiac-targeted mRNA delivery, assess long-term efficacy/safety, and design early-phase trials for ARVC and broader desmosomal cardiomyopathies.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Treatment/Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study with human genetic discovery and mouse models
- Study Design
- OTHER