Grant Award Details
iPS Glial Therapy for White Matter Stroke and Vascular Dementia
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.
Grant Application Details
- iPS Glial Therapy for White Matter Stroke and Vascular Dementia
This cell line will target recovery in ischemic white disease, a progressive dementing condition with no current therapy by developing a new stem line, iPS-glial enriched progenitors (iPS-GEPs).
This cell line will target tissue repair and recovery in ischemic white disease/vascular dementia, a chronically progressive and dementing condition with no current therapy.
Major Proposed Activities
- Efficacy. 1) Determine most efficacious iPS-GEP line; 2) Test efficacy in chronic white matter stroke; 3) Test efficacy for transplant location; 4) Test dose response; 5) Test efficacy in aged mice
- Mechanism of Action. 1) Determine cell intrinsic vs extrinsic effects; 2) Identify expression profile of iPS-GEPs during tissue repair; 3) Identify molecular systems that produce recovery of function
- Assay Development.: 1) Qualify identity, purity, safety and stability assays for iPS-GEPs
- Biomarker Development. 1) Develop structural MRI biomarker of iPS-GEP repair of damaged white matter; 2) Develop resting state MRI biomarker of enhanced brain connectivity
Statement of Benefit to California:
Stroke is the leading cause of adult disability. White matter stroke occurs in the connecting areas of the brain. This entity is up to 30% of all stroke and the second leading cause of dementia. There is no therapy for this disease. White matter stroke damages the specialized cells that support brain connections, glial cells. The proposed studies develop a specifically tailored stem cell therapy for tissue repair in white matter stroke, an induced pluripotent glia cell.
Source URL: https://www.cirm.ca.gov/our-progress/awards/ips-glial-therapy-white-matter-stroke-and-vascular-dementia