# Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders > **NIH NIH U01** · FOX CHASE CHEMICAL DIVERSITY CENTER, INC · 2021 · $1,412,771 ## Abstract 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 t... ## Key facts - **NIH application ID:** 10210993 - **Project number:** 1U01AG068823-01A1 - **Recipient organization:** FOX CHASE CHEMICAL DIVERSITY CENTER, INC - **Principal Investigator:** Allen Bernard Reitz - **Activity code:** U01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $1,412,771 - **Award type:** 1 - **Project period:** 2021-07-01 → 2026-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10210993 ## Citation > US National Institutes of Health, RePORTER application 10210993, Therapeutics targeting TDP-43 to treat Alzheimer's disease and related disorders (1U01AG068823-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210993. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*