Human iPSC-derived neural progenitor cells rescue motor function and brain pathology in symptomatic Canavan disease mice.

Abstract

Canavan disease (CD) is a severe neurodegenerative disorder caused by aspartoacylase (ASPA) deficiency, leading to N-acetyl-L-aspartic acid (NAA) accumulation and spongy degeneration. While several therapeutic candidates improve outcomes in CD mouse models when delivered before symptom onset, there remains a need for treatments targeting established disease pathology. Here, we demonstrate that transplantation with human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) expressing a functional ASPA gene (ASPA iNPCs) can rescue disease manifestations in symptomatic CD (Nur7) mice. When administered at postnatal day 21 (P21), ASPA iNPCs successfully engrafted, differentiated into neural lineage cells, and restored ASPA activity as revealed by reduced NAA level. Transplanted mice showed a significant reduction in brain and cerebrospinal fluid (CSF) NAA levels, decreased vacuolation across multiple brain regions, improved myelination, and enhanced motor function 6-month post-transplantation. Our findings demonstrate that ASPA iNPC transplantation can effectively reverse established CD pathology, suggesting therapeutic potential for treating symptomatic patients.