U01AG088113

Development of EP2 receptor antagonist to treat Alzheimer's disease - Lay summary

Alzheimer's disease (AD) is the leading cause of dementia in the elderly.

Currently, about 6.5 million Americans are living with AD.

Alzheimer’s and other dementias are estimated to cost the US $321 billion per year and this number is expected to 1 trillion by 2050, yet no small molecule therapeutic agent on the horizon that clearly alters the disease progression and inevitable cognitive decline.

The small molecule drugs and anti-bodies that have been developed based on the amyloid cascade hypothesis showed a limited (if any) disease modifying benefit so far.

Thus, it would be very important to validate novel drug targets and small molecules that work through a novel mechanism of action for future AD therapy.

Neuroinflammation is recognized as a key phenotype in the AD brain that is associated with the development of dementia.

Prostaglandin-E2 receptor EP2, which acts downstream of complex signaling by cyclooxygenase-2 (COX-2) appears as a key driver of neuroinflammation.

Activation of this receptor further induces COX-2 creating a vicious reactive cycle in the brain.

We have recently developed a suite of small-molecule antagonists for this receptor and derived a proof-of-concept in 5XFAD mouse models demonstrating antagonism of EP2 attenuates neuroinflammation and the amyloid load in the brain.

Moreover, we have validated that EP2 receptor antagonism is associated with cognition sparing benefits in acute brain injury models of status epilepticus and a peripheral inflammatory sepsis model.

We have identified several preclinical lead candidates for development into a clinical lead and candidate drug to mitigate neuroinflammation and cognitive deficits in Alzheimer’s patients.

We now propose to define PK/PD relations of the lead EP2 antagonists on Alzheimer’s pathology markers in the brain and determine PK/PD relation on the AD relevant biomarkers in the blood (plasma), CSF and the brain tissue in two different mouse (5XFAD and APPSAA) models that display features of early-onset of AD (EOAD) and late-onset of AD (LOAD) in human.

Furthermore, we proposed to conduct drug development studies to determine therapeutic index and NOAEL for the lead EP2 antagonist and complete all other IND-enabling studies required by the FDA.

Our overall goal is to achieve a disease modifying efficacy by the EP2 drug that delays the progression of Alzheimer’s dementia at least by 5 years.

We envision that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD that will bypass the adverse cardiovascular events found with chronic dosing of COX-2 drugs.

Emory 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]

Atlanta, Georgia 30322 United States

Single Zip Code

Alzheimer's Drug-Development Program (U01 Clinical Trial Optional) (PAR-22-047)

Amendment Since initial award the total obligations have increased 80% from $1,737,244 to $3,129,550.