Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy

Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI. We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6 × 1012 genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function. Median follow-up time was 45 months (n = 4, three females and one male; age range: 5–10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%–67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges. A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI. This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research. [Display omitted] •Long-term data of AAV-mediated liver-directed gene therapy in patients with MPS VI•Sustained ARSB expression and modest increase in urine glycosaminoglycans•Endurance, pulmonary and cardiac function showed no changes despite ERT interruption Mucopolysaccharidosis type VI (MPS VI) is a rare lysosomal storage disease due to arylsulfatase B (ARSB) deficiency that leads to a multisystem accumulation of glycosaminoglycans (GAGs). Current treatment based on weekly infusions of enzyme replacement therapy (ERT) is unsatisfactory. In this study, after the discontinuation of ERT, MPS VI individuals received a single intravenous infusion of an AAV vector that delivered the gene encoding ARSB to the liver. AAV vector administration was safe and resulted in sustained ARSB expre