California's Stem Cell Agency

White matter stroke constitutes up to 30% of all stroke subtypes, and is the second leading cause of dementia (vascular dementia). White matter stroke occurs as small infarcts in the brain and progresses over years. There is no specific therapy for white matter stroke and no therapy that enhances the brain's ability to recover in this disease. White matter stroke, unlike other stroke subtypes, does not destroy neurons but instead glial cells (astrocytes), axons and their ensheathing elements (oligodendrocyes and myelin). Generation of human induced pluripotent stem cells (hiPSCs) has created a vast potential for regenerative medicine. This grant developed a unique stem cell therapy for neural repair after white white matter stroke. By treating hiPSC-derived neural progenitors with a short exposure of a small molecule, these cells are permanently biased to differentiate predominantly into glial cells (immature astrocytes). This process allows rapid and efficient production of hiPSC-Glial Enriched Progenitors (hiPSC-GEPs), and scale up for a clinical application. Therefore, a cell-based therapy that can replace lost glia and induce structural repair in white matter stroke is of great promise. After the successful completion of this grant, researchers were able to demonstrate the outstanding repair capabilities of hiPSC-GEPs after white matter stroke and narrow down the key molecular players of white matter repair associated with hiPSC-GEPs. Dr. Carmichael and collaborators were able to determine the appropriate dose, therapeutic time window after stroke and location in the brain to transplant hiPSC-GEPs to restore neurological functions lost due to white matter stroke, in aged and young adult mice. They have successfully established limits for the qualification assays (identity, purity, safety, stability) and demonstrated reliable and safe good manufacturing practices for a therapeutic product for future clinical trials and movement toward IND.