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Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders

Award Number: U01AG068823
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders - TDP-43 is a mixed proteinopapthy in Alzheimer’s disease (AD), AD-TDP, based on substantial epidemiological data correlating TDP-43 inclusions with cognitive decline in AD patients. TDP-43 associated AD has been termed as limbic-predominant age-related TDP-43 encephalopathy (LATE) as well as other acronyms, underlying the newly-recognized importance of TDP-43 in AD (AD-TDP). AD is the most common cause of mid- to late-life cognitive impairment and dementia, afflicting ~30 million people worldwide Based on an extensive review of clinical and pathological studies, TDP-43 proteinopathy is associated with an amnestic dementia syndrome that occurs in older adults. A statistical analysis of attributable risk suggests that TDP-43 associated AD is a major public health issue accounting for up to 20% of cases of clinically diagnosed AD dementia. This TDP-43 proteinopathy is a distinct clinical and pathological entity from other TDP-43 associated diseases that may also be treatable with a TDP-43 targeted therapy, such as amyotrophic lateral sclerosis (ALS) and certain forms of frontotemporal lobar degeneration (FTLD-TDP). Therefore, successful completion of this project has the potential to identify TDP-43-based therapeutics for the treatment of other diseases where TDP-43 plays a major and causative role. We have discovered small molecules that bind to TDP-43 in such a way as to inhibit binding of RNA to TDP-43 and prevent TDP-43 aggregation, with activity suggestive of a therapeutic effect in three models: (1) human wild-type and mutant TDP-43 expressed in Drosophila, (2) induced motor neurons (iMNs) from C9orf72 patient-derived iPSCs, and (3) mice expressing human TDP-43 (Thy1 promotor). Evidence from 2-D NMR studies and computational docking analysis suggests that these inhibitors are binding to ribonucleotide recognition motif RRM2 which contains one of the amino acids involved in a critical and functionally-relevant salt bridge with RRM1. A recent PET imaging study describes a metabolic marker to potentially select AD-TDP patients for clinical trials based on ratios of FDG imaging in different regions of the brain. In this project we seek to discover, validate and develop new small- molecule inhibitors of nucleic acid binding to TDP-43 and TDP-43 aggregation inhibitors to treat AD-TDP. Aim 1 is the optimization of in vitro potency and drug-like properties of novel TDP-43 ligands including penetration into the brain and acceptable half-life and safety measures using a comprehensive battery of pharmaceutical industry-standard assays and criteria. Aim 2 involves target engagement studies using hTDP-43 transfected in HEK293T cells, patient-derived induced motor neurons from iPSCs, dynamic light scattering analysis of aggregation, and X-ray crystallography of ligands bound into TDP-43. Aim 3 is evaluation in animal models of TDP-43 pathology, initially using a Thy1 promoter followed by a hTDP-43 based mouse model that demonstrates cognitive impairment in the absence of locomotor deficits. Aim 4 includes IND-enabling studies, scale-up synthesis, multi-species PK and rodent toxicity.


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 = $0 )
2026	2025	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	5	5/28/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,438,738 )
2025	2025	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	001	5	7/16/2025	NON-COMPETING CONTINUATION	$1,438,738
2025	2024	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	4	10/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,438,738

Issue Date FY: 2024 ( Subtotal = $1,363,709 )
2024	2024	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$1,363,709
2024	2023	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	3	10/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,363,709

Issue Date FY: 2023 ( Subtotal = $1,365,008 )
2023	2023	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	3	7/25/2023	NON-COMPETING CONTINUATION	$1,365,008
														Subtotal = $1,365,008

Issue Date FY: 2022 ( Subtotal = $2,104,964 )
2022	2022	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	002	2	8/8/2022	SUPPLEMENT FOR EXPANSION	$409,375
2022	2022	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	001	2	7/8/2022	NON-COMPETING CONTINUATION	$1,386,046
2022	2021	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	1	1/10/2022	NEW	$309,543
														Subtotal = $2,104,964

Issue Date FY: 2021 ( Subtotal = $1,103,228 )
2021	2021	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Aging Research	000	1	6/23/2021	NEW	$1,103,228
														Subtotal = $1,103,228

Grand Total All Awards = $7,375,647

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Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders

Award Number: U01AG068823

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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