Clinical and biochemical correction of a patient with neurodegenerative Mucopolysaccharidosis IIIA using hematopoietic stem cell gene therapy.

Autologous haematopoietic stem cell gene therapy (HSC-GT) is an emerging therapy for treatment-refractory neurodegenerative lysosomal storage disorders (LSD). Mucopolysaccharidosis IIIA (MPSIIIA) is a devastating LSD where pathogenic variants in the SGSH gene lead to toxic heparan sulfate accumulation, inflammation and cell death. Children present with developmental delay, neurodegeneration, significant behavioural disturbance, and die in late teens. We report 80-month outcomes for a patient with severe MPSIIIA following treatment with investigational autologous HSC-GT (OTL-201), at 30-months of age. Haematopoietic stem and progenitor cells (HSPC) were collected from peripheral blood following mobilisation with G-CSF and Plerixafor. HSPC were transduced with a lentiviral vector containing the SGSH gene and the CD11b promoter. The product was infused following myeloablative conditioning with busulfan. Product engraftment was rapid, with production of sustained supra-physiological SGSH enzyme measured in leukocytes, plasma and cerebrospinal fluid (CSF), and reductions in substrate heparan sulfate to within the normal range in urine, plasma and CSF. Neurocognitive outcomes on the Bayley Scale of Infant Development (BSID-III) and parental-reported outcomes showed improvements compared to natural history. This demonstrates sustained long-term efficacy and safety of HSC-GT in a patient with severe MPSIIIA, setting the scene for a phase I/II clinical trial in younger patients.