Abstract Details

Title Development of Therapy for Canavan Disease Using Human Induced Pluripotent Stem Cells

Topic Child Neurology and Developmental Neurology

Presentation(s) S39 - Child Neurology and Developmental Neurology (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

Background CD is a fatal leukodystrophy caused by mutation of the aspartoacylase (ASPA) gene, which leads to deficiency in ASPA activity, accumulation of the substrate N-acetyl-L-aspartate (NAA), demyelination, and spongy degeneration of the brain. There is neither a cure nor a standard treatment for this disease.

Objective To develop a potential cell-based therapy for Canavan Disease (CD) using human induced pluripotent stem cells (iPSCs).

Design/Methods In this study, we established human iPSC-based cell therapeutic candidates for CD. To facilitate the transfer of the cell therapeutic candidates to the clinic, we first established GMP-compatible processes for human iPSC derivation, expansion, and differentiation. We then generated iPSCs from CD patient fibroblast cells and differentiated these iPSCs into iNPCs using the GMP-compatible processes we established. To reconstitute ASPA activity which is deficient in both CD patients and mouse models, we developed ASPA iNPCs by introducing a functional ASPA gene through lentiviral transduction. We transplanted the ASPA iNPCs into CD (Nur7) mouse brains.

Results We have demonstrated that research-grade NPCs derived from CD patient iPSCs that were transduced with a functional ASPA gene are able to ameliorate disease phenotypes in a CD (Nur7) mouse model in our developmental stage study. The therapeutic effect is long-lasting, showing no diminishing effect by 6 months compared to 3 months post-transplantation.

Conclusions This study provides important preclinical efficacy data for developing a therapeutic candidate for CD, a devastating leukodystrophy that has neither a cure nor a standard treatment. This is the first application of human iPSC technology in developing a stem cell therapy for CD. It provides a robust proof-of-principle for cell therapy development of this and other diseases of this kind. The feasibility and efficacy study presented here represents a critical step toward bringing the human iPSC-derived cellular products into the clinic for the treatment of CD.

Authors/Disclosures
Neal Prakash, MD, PhD, FAAN (City of Hope) PRESENTER	Dr. Prakash has nothing to disclose.
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