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Human iPSC-Derived Chimeric Antigen Receptor Macrophages to Modulate Inflammation and Combat Tau-Induced Pathology

Award Number: R61AG090358
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Human iPSC-Derived Chimeric Antigen Receptor Macrophages to Modulate Inflammation and Combat Tau-Induced Pathology - ABSTRACT Neurodegenerative diseases like Alzheimer's and related dementias (ADRD) manifest with chronic inflammation and tau pathology. Passive immunotherapies have shown some success in clinical trials, but significant disease improvement has not been achieved to date. The rapid advancement and clinical application of immune cell based therapies in oncology has opened the door to developing innovative new cell therapies to treat neurodegeneration. Monocytes and derivative macrophages (MΦ) engineered with chimeric antigen receptors (CAR-MΦ) have emerged as a promising candidate for allogeneic cell-based cancer immunotherapy. MΦ are unique from other immune cells in their capacity for tumor and tissue infiltration, and ability to phagocytosis extracellular entities including proteins, pathogens, and whole cells. The use of primary MΦ derived from patient blood is challenging as these cells cannot be engineered and expanded ex vivo like T or NK cells, making complex genetic engineering maneuvers nearly impossible. We recently developed an optimized process for production of CAR MΦ from human induced pluripotent stem cells (iPSC). Human iPSC are amenable to complex genome engineering, and we have established a scalable process for production of genetically engineered MΦ (iMΦ) for oncology applications. Here we propose redirecting our platform toward treatment of Alzheimer's disease (AD). Specifically, we will evaluate a curated list of novel iMΦ-specific CAR designs for targeting the pathogenic Tau protein and evaluate their function using a battery of biochemical and in vitro assays. Additionally, as inflammation is a key contributor to AD pathology and also a potential risk associated with transfer of immune cells to the central nervous system, we will pursue a two-pronged approach to address these challenges. First, we will utilize multiplex base editing in iPSC to deactivate key inflammatory genes in derivative iMΦ, thus rendering them inert in their ability to instigate counterproductive inflammation. Second, we will incorporate a CAR activation-responsive genetic element in our vector that allows for selective production and secretion of our recently published high potency and high selectivity TNFR1 antagonist, thus achieving an additional layer of inflammatory control specifically at the sites of Tau mediated inflammation. The collective result will be a novel, scalable, allogeneic cell platform capable of addressing both Tau mediated pathology and associated inflammation.


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 = $734,778 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	001	2	2/26/2026	NON-COMPETING CONTINUATION	$73,477
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	000	2	1/14/2026	NON-COMPETING CONTINUATION	$661,301
														Subtotal = $734,778

Issue Date FY: 2025 ( Subtotal = $734,778 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	1	1/14/2025	NEW	$734,778
														Subtotal = $734,778

Grand Total All Awards = $1,469,556

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Human iPSC-Derived Chimeric Antigen Receptor Macrophages to Modulate Inflammation and Combat Tau-Induced Pathology

Award Number: R61AG090358

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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