R01AG075084

Preventing Tau Uptake by Novel Inhibitors of Tau Binding to LRP1 - Project Summary

Several neurodegenerative diseases, such as Alzheimer's Disease (AD), are characterized by the spread and aggregation of the protein tau. Tau aggregates, also known as neurofibrillary tangles (NFTs), accumulate throughout the brain of patients and lead to dementia. Currently, there are no effective treatments for tauopathies. Approaches that have been considered, such as tau antibodies and antisense oligonucleotides, directly target tau. However, the complexity of tau cell biology makes this approach challenging.

A completely novel approach is to take advantage of the tau spreading pathway. The spread of NFTs correlates with disease progression and is a likely mediator for the observed neurotoxicity. Recently, a cellular receptor called LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) has been identified as a regulator of the tau spread pathway. Knockdown of LRP1 prevents tau spread in human IPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important entry point for disease intervention.

Therefore, the main objective of this project is to identify small-molecule chemical probes that prevent the binding of tau to LRP1. The hypothesis is that these molecules would serve as key starting points for novel therapeutics. In preliminary work, the primary interaction surface for tau on LRP1 has been identified, and a TR-FRET high-throughput screening (HTS) assay has been developed to identify compounds that can disrupt this interaction. The assay has been optimized to a 1536-well format, and a pilot screen of 5,000 compounds has been conducted with excellent performance. The hit rate from this screen was approximately 0.4%, with a Z' value of ~0.7.

To fully develop this work, three aims are proposed. In Aim 1, the TR-FRET assay will be used to screen a 420,000 chemical library, and in parallel, an affinity screen of a 4.4-billion-member DNA encoded library leveraging the Delopen platform (Wuxi AppTec) will be conducted. In Aim 2, hit selection will be narrowed down using orthogonal and novel biochemical profiling assays to determine the mechanism of action. Finally, in Aim 3, hits will be validated with advanced biophysical and cell-based assays.

It is expected that this multi-pronged approach will identify multiple chemical series with different mechanisms of action. Subsequent hit expansion efforts will produce chemical probes with properties suitable for testing the hypothesis that small molecule LRP1-tau inhibitors can prevent tau uptake and spread. In future studies, the intention is to develop these probes into drugs that prevent tau spreading in tauopathies such as AD. With the critical path testing funnel in place, it is anticipated that selective in vitro hits can be rapidly obtained and evaluated, exploring their activity and suitability as starting points for hit-to-lead studies and for future in vivo evaluation in animal models and eventually patients.

Santa Barbara University Of California

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]

California United States

State-Wide

Drug Discovery For Nervous System Disorders (R01 Clinical Trials Not Allowed) (PAR-19-147)

Amendment Since initial award the total obligations have increased 277% from $885,722 to $3,334,837.