Summary: Canavan disease (CD) is a devastating neurological disease that lacks effective therapy. Because CD is caused by mutations of the aspartoacylase (ASPA) gene, we introduced the wild-type (WT) ASPA gene into patient iPSCs through lentiviral transduction or CRISPR/Cas9-mediated gene editing. We then differentiated the WT ASPA-expressing patient iPSCs (ASPA-CD iPSCs) into NPCs and showed that the resultant ASPA-CD NPCs exhibited potent ASPA enzymatic activity. The ASPA-CD NPCs were able to survive in brains of transplanted CD mice. The engrafted ASPA-CD NPCs reconstituted ASPA activity in CD mouse brains, reduced the abnormally elevated level of NAA in both brain tissues and cerebrospinal fluid (CSF), and rescued hallmark pathological phenotypes of the disease, including spongy degeneration, myelination defects, and motor function impairment in transplanted CD mice. These genetically modified patient iPSC-derived NPCs represent a promising cell therapy candidate for CD, a disease that has neither a cure nor a standard treatment.
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