Novel TRPV4-Targeted Therapy for Arrhythmic Cardiomyopathy

Unmet Need

Arrhythmic cardiomyopathy (ACM) is a life-threatening condition characterized by fatty-fibrotic remodeling of the heart muscle, leading to arrhythmias, heart failure, and sudden cardiac death. While 60% of ACM cases are linked to known genetic causes, the etiology remains unclear for the remaining patients. This gap in understanding has hindered the development of targeted therapies and as a result 25% of affected individuals do not survive to adulthood. There is an urgent need for novel treatments for ACM and related cardiac conditions, guided by a deeper mechanistic understanding of disease processes.

Technology

Duke inventors have developed a novel therapeutic approach to treating ACM and related cardiac arrhythmias. This treatment utilizes clinical-stage compounds with established safety profiles in patients with heart failure. Specifically, the inventors identified that calcium-mediated arrhythmic depolarizations can be prevented by inhibiting TRPV4 current, a new target generated from studying a familial form of ACM with a previously unknown genetic cause. The efficacy of TRPV4 inhibition has been demonstrated in patient-derived cardiac myocyte cell lines and animal models of ACM where small-molecule TRPV4 inhibitors successfully treated disease. This innovation offers a promising path toward novel, mechanism-informed therapies for arrhythmic cardiomyopathies, with multiple compounds ready for clinical development.

Other Applications

This technology could also be used to treat other cardiac diseases marked by TRPV4 dysregulation, such as ischemia and conditions with a pathological Ca²⁺ leak, like catecholaminergic polymorphic ventricular tachycardia.

Advantages

• Clinically safe compound: Utilizes a clinical-stage compound with a proven safety profile in prior cardiovascular trials, enabling faster translation to clinical applications and reducing risk.
• First-in-class approach: Introduces a pioneering strategy to suppress intracellular calcium leak, a known determinant of arrhythmia, offering a treatment option guided by mechanistic understanding of disease.
• Validated molecular target: TRPV4 as a novel and actionable molecular target for arrhythmic cardiomyopathies, with efficacy demonstrated in patient-derived samples and animal models of disease.