iPSC-derived neural precursor cells engineering GBA1 recovers acid b-glucosidase deficiency and diminishes & alpha;-synuclein and neuropathology

Mutations in GBA1, encoding the lysosomal acid b-glucosidase (GCase), cause neuronopathic Gaucher disease (nGD) and pro-mote Parkinson disease (PD). The mutations on GBA1 include deletion and missense mutations that are pathological and lead to GCase deficiency in Gaucher disease. Both nGD and PD lack disease-modifying treatments and are critical unmet medical needs. In this study, we evaluated a cell therapy treatment using mouse iPSC-derived neural precursor cells (NPCs) engineered to overexpress GCase (termed hGBA1-NPCs). The hGBA1-NPCs secreted GCase that was taken up by adjacent mouse Gba ?/- neurons and improved GCase activity, reduced GCase substrate accumulation, and improved mitochondrial func-tion. Short-term in vivo effects were evaluated in 9H/PS-NA mice, an nGD mouse model exhibiting neuropathology and a-synuclein aggregation, the typical PD phenotypes. In-travenously administrated hGBA1-NPCs were engrafted throughout the brain and differentiated into neural lineages. GCase activity was increased in various brain regions of treated 9H/PS-NA mice. Compared with vehicle, hGBA1-NPC-trans-planted mice showed X50% reduction of a-synuclein aggre-gates in the substantia nigra, significant reduction of neuroin-flammation and neurodegeneration in the regions of NPC migration, and increased expression of neurotrophic factors that support neural cell function. Together, these results sup-port the therapeutic benefit of intravenous delivery of iPSC-derived NPCs overexpressing GCase in mitigating nGD and PD phenotypes and establish the feasibility of combined cell and gene therapy for GBA1-associated PD.