TY - JOUR
T1 - Chimeric antigen receptor macrophages target and resorb amyloid plaques
AU - Kim, Alexander B.
AU - Xiao, Qingli
AU - Yan, Ping
AU - Pan, Qiuyun
AU - Pandey, Gaurav
AU - Grathwohl, Susie
AU - Gonzales, Ernesto
AU - Xu, Isabella
AU - Cho, Yoonho
AU - Haecker, Hans
AU - Epelman, Slava
AU - Diwan, Abhinav
AU - Lee, Jin Moo
AU - DeSelm, Carl J.
N1 - Publisher Copyright:
© 2024, Kim et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2024
Y1 - 2024
N2 - 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 β amyloid (Aβ) 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 Aβ-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 Aβ in AD.
AB - 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 β amyloid (Aβ) 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 Aβ-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 Aβ in AD.
UR - http://www.scopus.com/inward/record.url?scp=85188572670&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.175015
DO - 10.1172/jci.insight.175015
M3 - Article
C2 - 38516884
AN - SCOPUS:85188572670
SN - 2379-3708
VL - 9
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - e175015
ER -