PXD077620

PXD077620 is an original dataset announced via ProteomeXchange.

Title	Alpha Protein Kinase 3 Gene Therapy Restores Heart Function in Mouse and Human Models of Cardiomyopathy
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-06-25
AnnouncementXML	Submission_2026-06-25_02:51:09.208.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sean Humphrey
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-26 12:44:23	ID requested
⏵ 1	2026-06-25 02:51:09	announced

Dataset with its publication pending

submitter keyword: Phosphoproteomics,Proteomics, Cardiomyopathy

Sean J Humphrey
contact affiliation	Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia.
contact email	sean.humphrey@mcri.edu.au
lab head
Sean Humphrey
contact affiliation	Murdoch Children's Research Institute
contact email	sean.j.humphrey@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD077620
     1. Label: PRIDE project
     2. Name: Alpha Protein Kinase 3 Gene Therapy Restores Heart Function in Mouse and Human Models of Cardiomyopathy