RF1AG074256

Intranasal Treatment of Stem Cell-Derived Extracellular Vesicles for Alzheimer's Disease - Project Summary

This project's principal goal is to develop a non-invasive, extracellular vesicle (EV) based therapeutic strategy for improving brain function in Alzheimer's disease (AD). A novel approach that investigates the efficacy of intranasal (IN) administration of therapeutic EVs generated from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) in mouse models of AD is proposed.

The scientific premise is that hiPSC-derived EVs (hiPSC-EVs) carrying a cargo of beneficial miRNAs and neuroprotective proteins can activate advantageous signaling pathways in target cells, positively modulate the brain microenvironment, microglia, and neurogenesis in the brain, and improve brain function after injury or disease. Notably, preliminary studies have shown that IN administration of hiPSC-EVs results in their incorporation by neurons and microglia in virtually all brain regions in 5XFAD mice and leads to better cognitive and mood function, higher levels of hippocampal neurogenesis, and reductions in oxidative stress, neuroinflammation, and amyloid deposits.

This project, using mouse models of AD, will test the hypothesis that IN administration of hiPSC-derived EVs: (I) in the early stage of AD will maintain better cognitive and mood function; and (II) in the advanced stage of AD will reverse cognitive and mood dysfunction with significant modulation of neuropathology.

Studies in Specific Aim 1 will employ 5XFAD mice and investigate whether intervention with hiPSC-EVs in the early stage of AD would maintain better cognitive and mood function and whether such positive effects persist for prolonged periods. Investigations in Specific Aim 2, using both 5XFAD and A-beta-knock-in mice, will test whether IN administration of hiPSC-EVs in the advanced stage of AD would reverse cognitive and mood dysfunction.

Specific Aim 3 studies will ascertain the role of microglial modulation in hiPSC-EV mediated improvements in cognitive and mood function in 5XFAD mice through selective microglia depletion using PLX5622 introduced through diet. Studies in Specific Aim 4 will first examine changes in the anti-inflammatory property of hiPSC-EVs with knock-down or overexpression of specific miRNAs and proteins, using hiPSC-derived microglia cultures. Next, the effects of IN administration of hiPSC-EVs overexpressing the select miRNA and/or protein having robust anti-inflammatory activity will be tested in 6-month-old 5XFAD mice to determine whether such a strategy would improve the therapeutic benefits of hiPSC-EVs in the advanced stage of AD. Both male and female mice will be employed.

The hippocampus and the medial prefrontal cortex will be rigorously examined for the various cellular and molecular changes mediated by hiPSC-EVs in all aims. Particularly, whether functional improvements with hiPSC-EV treatment would comprise the suppression of oxidative stress and neuroinflammation, a higher level of hippocampal neurogenesis, and reductions in amyloid-beta deposits, p-tau, synapse loss, and neurodegeneration will be ascertained.

The proposed translational research studies are highly conducive to developing an allogeneic hiPSC-EV therapy for AD.

Texas A & M University System Health Science 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]

College Station, Texas 778430001 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the End Date has been extended from 07/31/25 to 07/31/27 and the total obligations have increased 64% from $2,212,694 to $3,620,000.