Human iPSC-derived neural progenitor gene therapy improves outcomes in a neuropathic lysosomal disease.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a neuropathic lysosomal storage disorder caused by SGSH mutations leading to heparan sulfate accumulation in the brain. This drives progressive cognitive decline, neuroinflammation, and behavioral abnormalities. No effective disease-modifying therapy exists, as current approaches fail to deliver sufficient enzyme to the brain or halt neurodegeneration. Here, we report a neural stem cell gene therapy that achieves high enzyme delivery and restores cognitive function, likely through integration of healthy neural cells across multiple brain regions. Induced pluripotent stem cells were generated from healthy and MPS IIIA patient fibroblasts, differentiated into neural progenitor cells, and transduced with lentiviral vectors encoding codon-optimized SGSH and luciferase. Modified cells were bilaterally transplanted into the striatum of NSG-MPSIIIA mice at 2 months of age. Three months post-injection, behavioral and histological analyses demonstrated full correction of spatial working memory deficits and significant reductions in heparan sulfate storage and astrogliosis. This allogeneic, enzyme-expressing neural cell strategy addresses both enzyme deficiency and neurodegeneration, offering a promising therapeutic avenue for MPS IIIA and broader lysosomal storage disorders.