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

Abstract

Autologous hematopoietic stem cell gene therapy (HSC-GT) is an emerging therapy for treatment-refractory neurodegenerative lysosomal storage disorders (LSDs). Mucopolysaccharidosis IIIA (MPSIIIA) is a devastating LSD where pathogenic variants in the gene SGSH lead to toxic heparan sulfate accumulation, inflammation, and cell death. Children present with developmental delay, neurodegeneration, and significant behavioral 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. Hematopoietic stem and progenitor cells (HSPCs) were collected from peripheral blood following mobilization with granulocyte colony stimulating factor (G-CSF) and plerixafor. HSPCs were transduced with a lentiviral vector containing SGSH 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 parent-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 1/2 clinical trial in younger patients.