First-in-human intracisternal dosing of RGX-111 in severe MPS I is well-tolerated and generates sustained neurodevelopment without HSCT

Mucopolysaccharidosis type I (MPS I), caused by α-l-iduronidase enzyme (IDUA) deficiency, manifests multisystemic symptoms from tissue accumulation of undegraded glycosaminoglycans. Severe MPS I (Hurler syndrome) is associated with developmental delay and loss of neurocognition. Although IDUA enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation (HSCT) are standard therapies for Hurler syndrome, gene therapy represents potential alternative treatment of neurodevelopmental disease. We report more than 5 years of clinical, biochemical, and neurocognitive outcomes following a first-in-human, open-label, single-patient, single-administration of one intra-cisterna magna (ICM) RGX-111 (AAV9.CB7.hIDUA, 1E10 vector genomes/gram brain mass) in a 20-month-old boy with Hurler syndrome with two older affected siblings deceased from HSCT-related complications. The ICM procedure was safe and well-tolerated; treatment-emergent adverse events were mild and self-limiting. Crucially, serial brain imaging has been normal. He has never received a HSCT and continues with weekly IDUA infusions. Neurocognitive testing demonstrates ongoing acquisition of developmental abilities, with cognitive, speech, and motor age equivalents measuring one to two standard deviations below the normative mean. His neurodevelopment is significantly above the natural history of untransplanted Hurler syndrome patients. This single patient experience suggests central nervous system-directed gene therapy demonstrates therapeutic potential for severe MPS I and other genetic neurodegenerative diseases.