Intra cerebral administration of AAVrh-10 carrying human SGSH and SUMF1 cDNAs in children with MPSIIIA disease: Long term follow-up of a phase I–II trial

Abstract

Objective: Mucopolysaccharidosis type IIIA is a severe degenerative disease due to an autosomal recessive genetic defect in the gene coding for the lysosomal N- sulfoglycosamine sulfohydrolase (SGSH) whose catalytic site is activated by a sulfatase modifying factor (SUMF1). No effective treatment exists and an intra-cerebral gene therapy was developed using an AAV-2/rh.10-SGSH-IRES-SUMF1 vector that was administered in four children in a phase I/II clinical trial. The first 3 patients were close to 6 years and the last was 2.7 years old (median age=6,1 y) at treatment. All children were ambulatory but had already decreased cognitive abilities with brain atrophy detectable on MRIs at the time of treatment. In order to prevent elimination of transduced cells, an immunosuppressive treatment (Mycophenolate mofetil, Tacrolimus) was initiated before surgery and maintained either 8 weeks (Mycophenolate-mofetil) or throughout the follow-up (Tacrolimus, with progressive dose reduction). Methods: Yearly, neurological and cognitive performance (PEP, Vineland, TBAQ tests) as well as brain imaging were performed. Biological follow-up was done every 4 months and adverse events (AE) and severe adverse events (SAE) were recorded regularly. Results: Overall safety evaluation showed a good tolerance of the treatment with a total number of 6 SAE and 209 AE not related to the treatment nor to the procedure. Cognitive evolution, assessed by serial motor and cognitive assessment showed a persistent decline in abilities in the four included patients during follow-up, even if a transitory improvement of mood and sleep disorders was observed in all. Follow-up of brain MRI showed an increase of brain atrophy in all children. Conclusion: This first gene therapy trial using AAVrh-10 carrying human SGSH and SUMF1 cDNAs in MPSIIIA proved to be safe and well tolerated, but clinical and cognitive outcome of the four included children followed natural history of MPSIIIA.