Liver-targeted VPS33B gene therapy boosts survival to 80% in ARC syndrome mouse model without inducing tumors

The team engineered AAV constructs with liver-specific promoters and capsids to restrict VPS33B expression to hepatocytes in a conditional knockout model that recapitulates human ARC cholestasis, renal tubulopathy, and arthrogryposis. Systemic administration improved survival and reduced collagen deposition measured by Sirius Red staining, yet produced insertional activation events leading to hepatocellular carcinoma in 30% of animals. Switching to the liver-restricted cassette abolished detectable tumors at 12 months while preserving therapeutic efficacy, illustrating how promoter choice and capsid tropism jointly determine genotoxicity risk. This result aligns with prior clinical observations in SMA and hemophilia AAV trials where integration near oncogenes occurred but rarely progressed to malignancy when expression was tightly regulated. It also echoes the 2021-2023 FDA holds on early-generation vectors for ornithine transcarbamylase deficiency, underscoring that vector redesign rather than abandonment has become the dominant safety strategy for monogenic liver disorders. Remaining questions include durability of episomal expression beyond one year, potential immune responses to the transgene product in null patients, and scalability of GMP manufacturing for an ultra-rare indication affecting fewer than six UK births annually. Long-term GLP toxicology studies in larger species are required before an IND filing. Next steps outlined by the investigators involve dose-ranging studies in non-human primates followed by a first-in-human phase 1 trial restricted to infants with confirmed biallelic VPS33B mutations once vector integration profiles are fully mapped.