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

ABSTRACT: Truncating variants in Alpha Kinase 3 (ALPK3) cause severe cardiomyopathy for which there is no curative treatment. Here, we established an AAV-mediated gene replacement therapy to deliver full-length human ALPK3. This approach prevented cardiomyopathy development in neonatal Alpk3 mutant mice and reversed established pathology in adults. A deep proteomic interrogation demonstrated a reversal of more than 95% of the molecular signature of disease. Beyond ALPK3-deficient cardiomyopathy, we explored broader therapeutic potential based on ALPK3's regulatory role in proteostasis, a pathway commonly disrupted across cardiomyopathies. ALPK3 expression is dysregulated in cardiomyocytes harbouring titin truncating variants (TTNtv), which represent the most prevalent cause of dilated cardiomyopathy and share a common protein quality control network co-ordinated by ALPK3. Strikingly, AAV-ALPK3 completely restored contractile function in human cardiac organoids harbouring either ALPK3tv or TTNtv variants, demonstrating therapeutic efficacy across genetically distinct cardiomyopathies. These findings establish proof-of-concept for ALPK3 gene therapy in patients with ALPK3 cardiomyopathy while also revealing potential for indication expansion to TTNtv-associated cardiomyopathy, which is not amenable to conventional gene replacement therapy due to the extreme size of titin. These findings demonstrate the therapeutic potential of ALPK3-directed gene therapy as a potential curative treatment for patients with ALPK3 cardiomyopathy and other cardiomyopathies associated with disrupted proteostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Sean Humphrey  

LAB HEAD: Sean J Humphrey

PROVIDER: PXD077620 | Pride | 2026-06-25

REPOSITORIES: Pride