Wednesday, March 18, 2026 3/18/2026

Off-the-shelf CAR-Engineered Macrophage Therapy for Alzheimer’s Disease

Award Number: R61AG090384
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

Group Awards By:

View Award Description

Off-the-shelf CAR-Engineered Macrophage Therapy for Alzheimer’s Disease - Project Summary Alzheimer's disease (AD) affects 6.7 million Americans. Extracellular deposition of E-amyloid (AE) and accumulation of hyperphosphorylated-tau inside neurons are two primary culprits of AD pathology and targets for emerging AD therapies. Recent clinical trials of anti-AE monoclonal antibodies (mAbs) in AD patients showed AE deposition can be reversed resulting in significant slowing of cognitive decline. Yet, anti-AE immunotherapy comes with several shortcomings. These include need for recurring mAb infusions, staggering costs, and serious side effects in the form of brain bleeds and/or edema, and contraindications disqualifying a large number of patients. Chimeric antigen receptor (CAR) therapies have recently revolutionized several areas of oncology and hold high promise for adaptation in other medical fields including neurodegeneration, where CAR-engineered macrophages (Mĭs) can be used for targeted clearance of disease specific misfolded proteins and modulating neuroinflammation. A key issue in CAR-based therapies are their high costs resulting from in vitro engineering of patient-derived T cells or Mĭs and subsequent autologous implantation. This can be addressed using HLA- compatible, “off-the-shelf” human induced pluripotent stem cells (hiPSCs) as a platform for expressing disease specific CARs. This R61/R33 application proposes to develop a unique CAR-Mĭ therapy for AD based on “off- the-shelf” hiPSCs, which will be genetically programmed for fast and robust transdifferentiation into self- sustainable, macrophages/microglia (iMĭ) expressing CARs targeting AD specific proteins. Our CAR-iMĭs will be engineered to withstand CSF1R inhibition , which will be used to facilitate their brain homing. They also will be modified for attenuated inflammatory response and equipped with “kill switches” for therapy control. Our preliminary work for this grant application includes identification of five novel anti-AE clones binding AE deposits and effecting their clearance in APP/H3 mice by Fc-mediated microglia phagocytosis. We also have engineered a doxycycline-inducible genetic circuit expressing SPI1 and CEBPĮ transcription factors allowing for robust trans- differentiation of hiPSCs into iMĭ. Aims of the R61 phase are as follows: 1) to optimize iMĭ transdifferentiation protocol and characterize resulting iMĭ cells; 2) to engineer CARAE using scFv sequences from our novel anti- AE clones and express them in iMĭs; 3) to engineer an orthogonal CSF1 receptor, which will be constitutively active and resilient to pharmacological inhibition; 4) to reprogram hiPSC HLA to “cloak” the cells against the intact murine immune system permitting in vivo testing. Aims of the R33 phase will be as follows: 1) to produce CARAE-iMĭs by combining all singular genetic elements tested in the R61 phase and characterize CARAE-iMĭ biodistribution, brain homing and survival in vivo; 2) to test engagement and clearance of AE plaques by CARAE- iMĭs in APP/H3 and APP/H4 mice; 3) to characterize the transcriptomic profile of CARAE-iMĭs in APP/H3 and APP/H4 mice and explore effects of knocking-out genes, which are key to acquisition of MGnD phenotype and propagating inflammatory response; 4) to engineer and test “kill switches” for on demand activity control.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $805,720 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	1/28/2026	NON-COMPETING CONTINUATION	$725,149
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	2	2/26/2026	NON-COMPETING CONTINUATION	$80,571
														Subtotal = $805,720

Issue Date FY: 2025 ( Subtotal = $810,596 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	1	1/28/2025	NEW	$810,596
														Subtotal = $810,596

Grand Total All Awards = $1,616,316

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Off-the-shelf CAR-Engineered Macrophage Therapy for Alzheimer’s Disease

Award Number: R61AG090384

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer