PXD077802

PXD077802 is an original dataset announced via ProteomeXchange.

Title	Quantification of Human VPS33B expression in mouse liver via lentiviral transfection
Description	Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a lethal autosomal recessive disorder caused by deficiencies of VPS33B or VIPAS39 trafficking proteins. VPS33B deficiency in hepatocytes disrupts bile secretion, leading to progressive liver fibrosis, terminal liver disease and death of most ARC patients before the age of one year. Here, we developed a lentiviral gene therapy for ARC syndrome. Therapeutic vectors EF1-VPS (ubiquitous), LP1-VPS (liver-specific) and GFP controls were produced and tested in vitro in HepG2 VPS33B-/- cells. In vivo safety was assessed using neonatal heterozygous Vps33bLiver+/- mice. For efficacy experiments, Vps33bLiver-/- mice received neonatal intravenous injections combined with transient liver macrophage depletion and cholestasis was exacerbated using a 0.25% cholic acid diet. EF1-VPS and EF1-GFP vectors raised safety concerns, with 3 in 10 treated mice developing hepatocellular carcinomas, compared to none treated with the liver-specific vectors. Integration site analysis evidenced clonal expansion and Tox as a common vector integration locus in the 3 carcinomas. The safe LP1-VPS vector showed efficacy through significant improvement in survival, growth, and ARC-specific biomarkers. Microscopy liver analysis displayed reduced fibrosis and restoration of bile canalicular ultrastructure. These findings offer hope for ARC syndrome patients and serve as proof-of-concept for lentiviral gene therapy safety and efficacy studies in early-onset liver disorders.[
HostingRepository	PanoramaPublic
AnnounceDate	2026-04-29
AnnouncementXML	Submission_2026-04-29_09:33:14.703.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Wendy Heywood
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Xevo TQ-XS

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-29 09:29:49	ID requested
⏵ 1	2026-04-29 09:33:15	announced

no publication

submitter keyword: ARC syndrome, VPS33B, VIPAS39, lentiviral gene therapy, liver-specific gene therapy, hepatocyte gene transfer, LP1.VPS, cholestasis, liver fibrosis, mouse model, Vps33b knockout, neonatal intravenous injection, macrophage depletion, targeted proteomics, LC-MS/MS, MRM, VPS33B quantification, liver tissue, bile secretion, hepatocellular carcinoma, integration site analysis, translational medicine

Wendy Heywood
contact affiliation	University College london
contact email	wendy.heywood@ucl.ac.uk
lab head
Wendy Heywood
contact affiliation	University College London
contact email	wendy.heywood@ucl.ac.uk
dataset submitter

Panorama Public dataset URI