Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy
Year: 2026
Type: article
Abstract: . 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.
Source: Nature Cardiovascular Research
Institutions: Royal Children's Hospital, The University of Melbourne, Victor Chang Cardiac Research Institute, Murdoch Children's Research Institute, Australian Regenerative Medicine Institute, Monash University, Queensland University of Technology, Gladstone Institutes, University of California, Los Angeles, QIMR Berghofer Medical Research Institute, The University of Queensland
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Children’s Hospital of Wisconsin Research Institute, Children's Hospital Foundation, Murdoch Children's Research Institute, Australian Government, Novo Nordisk, State Government of Victoria, Novo Nordisk Fonden, Medical Research Council, National Health and Medical Research Council, Medical Research Future Fund
OpenAlex ID: W4412855230