Translating Pluripotent Stem Cell Therapies For Focal Brain Disorders

A major challenge for the clinical application of pluripotent stem cell therapy for neurodegenerative diseases is large-scale manufacturing and cryopreservation of neurons and glia that can be prepared for surgery with minimal manipulation. To address this obstacle, midbrain dopamine (iPSC-mDA) and forebrain (iPSC-FB) lineage neurons were derived from human induced pluripotent stem cells and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic neurons retained high-viability with gene, protein, and electrophysiological signatures consistent with that of the neuronal lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without sub-culturing into the 6-OHDA-lesioned rat and MPTP-lesioned nonhuman-primate models of PD. Grafted neurons retained midbrain lineage with extensive innervation of both rodent and monkey brain with no aberrant growth. Behavioral assessment in parkinsonian rats demonstrated significant reversal in functional deficits up to 6-months post-transplantation. In addition, cryopreserved iPSC-FB neurons grafted into the striatum of athymic NUDE rats survived and innervated distant anterior and posterior brain structures at 9-months post-grafting. These findings demonstrate a simple and efficacious surgical intervention to deliver cryopreserved iPSC-derived neurons for brain disorders and support translational development of pluripotent cell-based therapies in neurodegenerative disease.