Pharmacological rejuvenation of human hematopoietic stem cells

Abstract/Summary The goal of this application is to further develop a first-in-class therapeutic regimen that attenuates aging of human hematopoietic stem cells (HSCs). Aging of hematopoiesis in older adults often manifests as aging-associated anemia, progressive reduction in the immune response, and/or increased incidence of myeloid malignancy. These aging associated declines are in part attributed to the aging of hematopoietic stem cells (HSCs) and hematopoietic system that sustain our life-long production of quality red blood cells, immune cells and white blood cells. Previous studies have established, mostly in murine models, that elevated Cdc42 activity and loss of cell polarity serve as aging associated biomarkers for HSCs and targeting Cdc42 activity via a lead small molecule Cdc42- activity specific inhibitor, CASIN, can dose-dependently suppress elevated Cdc42 activity and loss of polarity of aged animals to functionally rejuvenate or attenuate aging of murine HSCs. CASIN thus has the potential to be further developed towards clinical applications to benefit human aging. The central hypothesis of this proposal is that targeting Cdc42 activity with the drug CASIN can restored Cdc42- regulated polarity and rejuvenate aged human HSCs ex vivo, which will benefit bone marrow HSC transplant patients. The proposed studies will develop the proof-of-principle of an intervention to rejuvenate aged blood forming system and validate CASIN in rejuvenating aged human HSC epigenetic clock and function at well-defined ex vivo conditions. The proposal will also test a clinically applicable closed circuit HSC manipulation apparatus for CASIN ex vivo treatment in future commercialization of this technology. Upon completion of the proposed studies, we expect our product will move closer to FDA IND filing and clinical trials in preventing or treating aging related functional decline of human blood system to benefit the lives of older adults.