Liver-Directed Adeno-Associated Virus–Mediated Gene Therapy for Mucopolysaccharidosis Type VI

BackgroundMucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts urine. MPS characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, hepatosplenomegaly. Enzyme replacement therapy (ERT) available but requires life-long costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton valves, compromised pulmonary function, corneal opacities.MethodsWe enrolled nine patients with 4 years age or older a phase 1/2 open-label gene study. After ERT was interrupted, each received single infusion adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially one three dose cohorts: low (three patients), intermediate (two high (four patients). The primary outcome safety; biochemical clinical end points secondary outcomes.ResultsThe infusions occurred without severe adverse events attributable the vector, meeting prespecified point. cohorts displayed stable serum ARSB approximately 20% mean healthy value returned 14 months after because urinary GAG. high-dose cohort had sustained 30% 100% modest GAG increase did not reach concentration at reintroduction needed. In group, there no deterioration for up 2 therapy.ConclusionsLiver-directed participants have dose-limiting side-effect event profile; treatment resulted expression over least 24 preliminary evidence disease stabilization. (Funded Telethon Foundation ETS, European Commission Seventh Framework Programme, Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT 2016-002328-10.)