Alpha protein kinase 3 gene therapy restores heart function in mouse and human models of cardiomyopathy
. 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.
Authors
- Neda R. Mehdiabadi (ORCID: https://orcid.org/0000-0003-1929-2034)
- Christina V. Theodoris (ORCID: https://orcid.org/0000-0003-1658-1447)
- Drew M. Titmarsh (ORCID: https://orcid.org/0000-0001-8379-6136)
- M Venkatesh (ORCID: https://orcid.org/0000-0002-2698-367X)
- James W. McNamara (ORCID: https://orcid.org/0000-0003-3754-6405)
- James E. Hudson (ORCID: https://orcid.org/0000-0003-0832-9356)
- Enzo R. Porrello (ORCID: https://orcid.org/0000-0001-6105-7463)
- Sean J. Humphrey (ORCID: https://orcid.org/0000-0002-2666-9744)
- Richard J. Mills (ORCID: https://orcid.org/0000-0001-9735-2595)
- David A. Elliott (ORCID: https://orcid.org/0000-0003-1052-7407)
- Brendan Griffen
- Hannah Huckstep (ORCID: https://orcid.org/0000-0001-5451-294X)
- Yinghan She
- Rebecca Sutton
- Ellen B. Keen
- Lina H.H. Le (ORCID: https://orcid.org/0009-0009-5368-8391)
Institutions
- Gladstone Institutes (US)
- Royal Children's Hospital (AU)
- Queensland University of Technology (AU)
- University of California, Los Angeles (US)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Victor Chang Cardiac Research Institute (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Teradyne (United States) (US)
- Australian Regenerative Medicine Institute (AU)
- Teledyne Technologies (Australia) (AU)
- Institute of Human Genetics (PL)
- Murdoch Children's Research Institute (AU)
- Monash University (AU)
- Victoria University (AU)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2026-08-19
- DOI
- https://doi.org/10.1038/s44161-026-00843-1
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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