R01AG074541

CGAS Inhibitors for Alzheimer's Disease Treatment - Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Amyloid-β (Aβ) and tau pathologies, along with neuroinflammation, are three major hallmarks of Alzheimer's disease. The majority of drug discovery efforts in the past decades have focused on targeting the Aβ pathology, but none have been successful in clinical trials. While tau pathology, not the Aβ pathology, has emerged to play a critical role in memory decline in AD, drugs targeting the direct effects of tau on neurons have also not been successful.

Compelling human genetic studies have linked the innate immune responses to an elevated risk of developing late-onset AD, supporting the targeting of microglia, resident immune cells in the brain, as the next-generation treatment for AD. We have shown that there is a critical role of cyclic GMP-AMP synthase (CGAS)-stimulator of interferon genes (STING) signaling in microglial toxicity and tau-mediated cognitive decline. Activation of CGAS, a major cytosolic dsDNA sensor, catalyzes the production of cyclic GMP-AMP (cGAMP), an extremely potent STING agonist, as the second messenger that activates the CGAS-STING pathway. This leads to the production of antiviral responses through the activation of interferon regulatory factors (IRFs) and the expression of cytokine and type I interferon genes.

We found that partial or complete genetic CGAS ablation protected against tau-mediated spatial learning and memory deficits in PS19 tau mice. Moreover, treatment with a small molecule inhibitor of CGAS reduced interferon responses, diminished microgliosis, and protected against cognitive deficits in an AD mouse model with tauopathy. We hypothesize that inhibiting CGAS activity will dampen neuroinflammation and maladaptive immune responses, protecting against AD-related deficits.

We propose to develop small molecule human CGAS (H-CGAS) inhibitors as novel microglial modulators to treat AD. In Aim 1, we will develop lead H-CGAS inhibitors starting with two known hits and determine whether these inhibitors effectively modulate the CGAS-STING pathway in cell-free and cell-based assays. We expect to identify new hits via hit expansion and synthesize over 200 analogs. Aim 2 focuses on the optimization of analogs, particularly a potent CGAS inhibitor called TDI-6570, which is a lead low nanomolar potent mouse CGAS (M-CGAS) inhibitor and possesses 10x less H-CGAS activity. We will design up to 50 new analogs, using results from structure-activity relationship (SAR), docking experiments, and in-silico calculations to maximize the lead quality. Completion of Aim 1 and Aim 2 will lead to 5 lead compounds for in vivo and efficacy studies.

In Aim 3, we will establish the pharmacokinetics (PK) and efficacy of H-CGAS inhibitors in a mouse model of tauopathy, as well as their efficacy in human stem cell-derived microglia and cerebral organoids with tauopathy. At the end of the proposed 5-year study, we anticipate identifying 1-2 lead H-CGAS inhibitors as tool compounds and a proof of principle to further advance as drug candidates to treat Alzheimer's disease and related neurological disorders.

Weill Medical College Of Cornell University

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]

New York, New York 100654805 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 398% from $847,498 to $4,220,539.