Hematopoietic Stem Cell-based CAR Macrophage for Alzheimer's Disease

Abstract Alzheimer’s disease (AD), characterized by amyloid beta (Aβ) plaque accumulation, remains a formidable challenge due to limited therapeutic interventions. Despite recent FDA approvals, Aβ targeting antibodies fail to significantly impact the clinical progression of cognitive decline and the treatment is associated with significant side effects. Recognizing these limitations, our project proposes a novel therapeutic approach leveraging the versatility and potency of Chimeric Antigen Receptor (CAR) technology, primarily known for its success in cancer treatment. We aim to develop a hematopoietic stem cell (HSC)- based CAR-Macrophage (CAR-M) therapy targeting Aβ aggregates while simultaneously reducing central nervous system (CNS) inflammation, a critical factor in AD pathology. Our preliminary work with CAR therapy against HIV demonstrates the potential for long- term efficacy, safety, and CNS trafficking of CAR-modified cells, laying the groundwork for this innovative AD treatment. The project is structured into two phases: the R61 phase focuses on developing and optimizing Aβ- targeting CAR-M for in vitro efficacy against Aβ aggregates and inflammation reduction, and investigate the safety and CNS trafficking of HSC-based CAR- M in vivo. The R33 phase aims to evaluate the short- and long- term efficacy of this therapy in mouse models of AD, assessing its impact on amyloid plaques, neuroinflammation, and behavioral outcomes. By combining the expertise of leaders in CAR therapy and AD research, this project represents a groundbreaking step towards a potentially transformative treatment for AD, addressing both the pathological hallmarks and the inflammatory environment contributing to disease progression.