A Human iPSC-based Cell Therapy for Canavan Disease

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Project Summary Canavan disease (CD) is a rare, autosomal recessive neurodevelopmental disorder that affects children from infancy. Most children with infantile-onset CD, the most prevalent form of the disease, will die within the first decade of life. There is neither a cure nor a standard treatment for this disease. CD is caused by genetic mutations in the aspartoacylase (ASPA) gene, which encodes a metabolic enzyme synthesized by oligodendrocytes in the brain. ASPA breaks down N-acetyl-aspartate (NAA), an amino acid derivative in the brain. The cycle of production and breakdown of NAA appears to be critical for maintaining the white matter of the brain, which consists of nerve fibers covered by myelin. Indications of CD include lack of ASPA activity, accumulation of NAA, myelination defect, and spongy degeneration (vacuolation) in the brain. The clinical symptoms include impaired motor function and mental retardation. There is currently no approved therapy for this condition. Therefore, there is a clear, unmet medical need for an effective therapy for CD. The development of human induced pluripotent stem cell (hiPSC) technology has opened exciting avenues for cell therapy. In our preliminary studies, we have used hiPSC technology to generate CD patient iPSCs and differentiated these iPSCs into neural progenitor cells (CD iNPCs). We then introduced a functional ASPA gene into CD iNPCs through lentiviral transduction to generate genetically engineered functional ASPA-containing iNPCs, termed ASPA iNPCs. In order to move the ASPA iNPC cell product to the clinic, we developed current Good Manufacturing Practice (cGMP)-compatible process to manufacture the ASPA iNPCs. The resultant ASPA iNPCs generated from three different CD patients were tested in a CD mouse model for efficacy and safety. After being transplanted into brains of CD mice, the ASPA iNPCs provided sustained ASPA activity, led to significantly lower NAA level, considerable rescue of spongy degeneration and myelination defect in the brain, and substantially improved motor function in the transplanted CD mice. Importantly, no tumorigenesis or other adverse effect was observed in the transplanted mice. These robust preclinical data provide strong rationale for the proposed study. The object of the proposed research is to establish a hiPSC-based cell therapy for CD. The cell products have proven in preclinical studies to be long lasting and efficacious with a favorable safety profile. We propose the following Specific Aims: Aim 1: To conduct IND-enabling qualification runs and perform final manufacturing of the ASPA iNPC cell products. Aim 2: To perform definitive preclinical efficacy and safety/tumorigenicity studies of the ASPA iNPC cell products. Aim 3: To obtain IND approval. Aim 4: To conduct a phase I clinical trial to establish the safety and feasibility of administering the ASPA iNPC cell products to CD patients. This study could lead to the development of a novel cell therapy for CD and demonstrate the feasibility of using hiPSC-based cell products for the treatment of similar diseases.