U01AG068823

Therapeutics Targeting TDP-43 to Treat Alzheimer's Disease and Related Disorders

TDP-43 is a mixed proteinopathy 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 approximately 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 promoter). 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.

FOX Chase Chemical Diversity Center

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Pennsylvania United States

State-Wide

Alzheimer's Drug-Development Program (U01 Clinical Trial Optional) (PAR-18-820)

Amendment Since initial award the total obligations have increased 569% from $1,103,228 to $7,375,647.