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.