U01AG074960

Novel Reengineered Microbiome-Based Biologic Therapy to Treat Cognitive and Behavioral Symptoms of Alzheimer's Disease and Related Dementias - Abstract

Our early-stage ADDP proposal aims to develop a novel genetically engineered bacterial biologic to treat the most common early symptoms of Alzheimer's Disease (AD), including cognitive impairment and other neuropsychological symptoms, such as anxiety and depression. This debilitating disease imposes a huge emotional, social, and financial burden on society. No effective disease-modifying AD drug exists to dampen the ASS and tau proteinopathies associated with disease progression. Current FDA-approved cholinergic and glutamatergic neurotherapeutics are very modest at best in rescuing memory in mild cognitive impairment (MCI) and prodromal or early stages of AD cases, and often worsen anxiety, apathy, depression, agitation, and other neurobehavioral symptoms, GI irritations, and even mortality.

Recent biological evidence indicates that AD is a neural circuit disorder. The onset and progression of cognitive and behavioral symptoms involve a deficiency in monoamine neurotransmitter signaling networks, including norepinephrine (NE) and dopamine (DA). Thus, we propose that restoring brain DA/NE inputs holds the excellent potential to be an effective approach to alleviating cognitive and behavioral deficits in AD and could even delay disease onset.

Currently, oral tablet dosing of L-DOPA/Carbidopa 3-4 times/day remains the most effective therapy at restoring brain DA/NE levels in humans. However, this repeated chronic pulsatile delivery causes severe side effects. Thus, our therapeutic hypothesis to address this unmet clinical problem is that systemic delivery of genetically engineered L-DOPA bacterial live-therapeutics (LDBL) will avoid large fluctuations in plasma L-DOPA and provide more consistent delivery of L-DOPA to the brain for restoring DA/NE to stable levels that better relieve AD symptoms without additional side effects.

Our proof-of-concept data support that 1) the genetically engineered probiotic E. coli Nissle 1917 strains (ECNL-DOPA) efficiently produce L-DOPA both in vitro and in vivo, 2) oral dosing of ECNL-DOPA readily colonizes the mouse gut, achieves a steady-state plasma L-DOPA level that corresponds to the clinically effective plasma level in humans, and increases L-DOPA and DA/NE levels in the brain of rodents and canines, and 3) ECNL-DOPA treatment leads to improved neurobehavioral outcomes and reduces ASS levels in AD animal models including canines.

The overarching goal of our patent-pending ADDP strategy is to optimize the lead LDBL and test its preclinical efficacy in alleviating the cognitive and behavioral deficits, such as apathy, of early AD. To achieve this goal, we will pursue the following specific aims:

(I) Optimize the lead LDBL for animal testing,
(II) Evaluate the chronic pharmacokinetic (PK) and safety profile of the lead LDBLs for preclinical efficacy studies,
(III) Determine in vivo pharmacodynamic (PD) efficacy of two lead LDBLs in transgenic (TG) AD rodent models, and
(IV) Assess the efficacy of the most effective lead LDBL in canine models of dementia.

Together, our unique therapeutic pipeline strategy involving chronic delivery of probiotic L-DOPA is expected to establish a new line of engineered microbiome-based monoamine neurotherapeutic modalities for AD-related dementias (ADRD).

University Of Georgia Research Foundation

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]

Athens, Georgia 306021589 United States

Single Zip Code

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

Amendment Since initial award the End Date has been extended from 05/30/27 to 05/31/27 and the total obligations have increased 304% from $1,459,176 to $5,896,816.