Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy

Vollständiger Abstract

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Abstract Truncating variants in the ALPK3 gene (encoding alpha protein kinase 3) cause severe cardiomyopathy for which no curative treatment exists 1–3 . Here we establish an adeno-associated virus (AAV)-mediated gene replacement therapy to deliver full-length human ALPK3 . AAV- ALPK3 prevented disease in neonatal Alpk3- mutant mice and reversed established pathology in adults, with proteomic analysis demonstrating reversal of more than 95% of the molecular disease signature. Beyond ALPK3 deficiency, we explored broader therapeutic potential based on ALPK3’s regulatory role in proteostasis, a pathway commonly disrupted across cardiomyopathies. ALPK3 expression is reduced in cardiomyocytes with TTN -truncating variants, the most prevalent cause of dilated cardiomyopathy, and the encoded titin protein has a protein quality control network in common with ALPK3. AAV- ALPK3 restored contractile function in human cardiac organoids with an ALPK3 - or TTN -truncating variant. These findings provide proof of concept for ALPK3 gene therapy in patients with ALPK3 cardiomyopathy and reveal potential for indication expansion to cardiomyopathies associated with TTN -truncating variants, which are not amenable to gene replacement therapy due to size limitations.