Alpha Protein Kinase 3 Gene Therapy Restores Heart Function in Mouse and Human Models of Cardiomyopathy

Abstract

Truncating variants in the Alpha Kinase 3 (ALPK3) gene have recently emerged as an important cause of genetic cardiomyopathy globally and here we demonstrate the efficacy and safety of a viral-based gene replacement therapy for ALPK3. Given the loss-of-function nature of these variants, we reasoned that a gene replacement approach would improve heart function in this patient population. We demonstrate that the delivery of full length ALPK3 via adeno-associated virus could restore contractile function in human cardiac organoids and in vivo mouse models carrying clinically relevant mutations in ALPK3. The role of disrupted proteostasis networks in multiple forms of genetic cardiomyopathy suggest that delivery this novel AAV-ALPK3 may provide functional benefit outside of cardiomyopathy induced by ALPK3. Titin truncating variants (TTNtv) are the most common cause of dilated cardiomyopathy, and interestingly also contributes to the M-Band protein quality control network coordinated by ALPK3. Notably, in human cardiac organoids carrying a TTNtv we observed that the ALPK3 gene therapy could completely restore contractile deficits. This opens the exciting prospect for indication expansion of AAV-ALPK3 into other forms of cardiomyopathy that currently have no therapeutic options.