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Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with\n                    <jats:italic>GBA1<\/jats:italic>\n                    <jats:sup>L444P\/P415R<\/jats:sup>\n                    and\n                    <jats:italic>GBA1<\/jats:italic>\n                    <jats:sup>L444P\/RecNcil<\/jats:sup>\n                    mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology.\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutation correction mediated by CRISPR\/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.\n                  <\/jats:p>","DOI":"10.7554\/elife.109518","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T14:30:21Z","timestamp":1770993021000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.109518","source":"Crossref","is-referenced-by-count":2,"title":["Patient-specific midbrain organoids with CRISPR correction recapitulate neuronopathic Gaucher disease phenotypes and enable evaluation of novel therapies"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8209-1185","authenticated-orcid":true,"given":"Yi","family":"Lin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01hcyya48","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Human Genetics, Cincinnati Children\u2019s 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