Chimeric antigen receptor macrophages target and resorb amyloid plaques

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of beta amyloid (A beta) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early -stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an A beta-targeting chimeric antigen receptor (CAR -Ms). When injected intrahippocampally, first -generation CAR -Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next -generation CAR -Ms that secrete M-CSF and self -maintain without exogenous cytokines. Cytokine secreting "reinforced CAR -Ms" have greater survival in the brain niche and significantly reduce plaque load locally in vivo. These findings support CAR -Ms as a platform to rationally target, resorb, and degrade pathogenic material that accumulates with age, as exemplified by targeting A beta in AD.