R01AG071656

A Clinical Trial of AAV2-BDNF Gene Therapy in Alzheimer's Disease - Project Summary/Abstract:

We propose to conduct a first-in-human clinical trial of BDNF gene therapy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), aiming to reduce neuronal loss and activate neuronal function. BDNF (brain-derived neurotrophic factor) is actively produced and utilized in cortical circuits throughout life to sustain neuronal function and circuits. In animal models of AD, BDNF builds new synapses, prevents neuronal death, and activates neurons. Thus, BDNF offers the potential to slow or actually reverse cognitive decline in established AD and MCI. Proof-of-concept studies have been performed in mice, rats, and rhesus monkeys.

Because BDNF is a relatively large and polar protein that does not cross the blood-brain barrier, we will use intraparenchymal gene therapy to deliver BDNF directly into the entorhinal cortex. BDNF will be neuronally trafficked into the hippocampus. BDNF will be delivered using adeno-associated serotype 2 vectors (AAV2), which have now been utilized in hundreds of patients in CNS gene therapy trials. We will utilize state-of-the-art methods for gene delivery, employing real-time MR guidance and convection-enhanced delivery (CED) in collaboration with the world leaders in this technology at Ohio State University (OSU).

A total of 12 patients (6 AD and 6 MCI) will be recruited from two clinical sites: UCSD and Case Western. All patients will undergo gene delivery at OSU. The primary outcome measure will be safety, together with secondary cognitive outcome measures that reflect memory-specific and global cognitive measures. Serum, CSF, and imaging biomarkers will be collected. If AAV2-BDNF gene delivery is safe and well-tolerated and exhibits possible cognitive benefits, we will advance to phase 2 trials. An IND for this program is under review by the FDA, and the trial will begin upon FDA clearance. Two dose groups will be studied: 3x1011 VG/mL and 1x1012 VG/mL.

Relevance: Effective disease-modifying therapies for AD and MCI have not been identified. BDNF gene delivery offers the potential to slow or reverse cognitive decline in established AD by building new synapses, stimulating neuronal function, and reducing neuronal death. Our approach also offers the potential for combination therapy with amyloid- and tau-modifying therapies.

San Diego 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

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the End Date has been extended from 04/30/26 to 04/30/27 and the total obligations have increased 255% from $1,201,473 to $4,266,904.