Project Grant R41AG073144

PROMOTING ADULT HIPPOCAMPAL NEUROGENESIS IN ALZHEIMER'S DISEASE USING AN ANTIBODY-BASED THERAPY - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A LOOMING PUBLIC HEALTH CRISIS THAT THREATENS MILLIONS OF PATIENTS' ABILITY TO EXPERIENCE HEALTHY AGING. IN ADDITION TO THE CHALLENGES THAT AD POSES TO PATIENTS, HEALTHCARE PROVIDERS AND CAREGIVERS, THERE IS ALSO TREMENDOUS ECONOMIC BURDEN ASSOCIATED WITH AD AND RELATED DEMENTIAS - ESTIMATED TO BE WELL OVER $200B/YEAR IN THE UNITED STATES ALONE. HUNDREDS OF ATTEMPTS TO DEVELOP THERAPIES TO HALT THE PROGRESSION OF OR REVERSE AD HAVE BEEN TRIED, BUT UNFORTUNATELY NONE HAVE BEEN SUCCESSFUL TO DATE. THE RESULTS OF THESE STUDIES STRONGLY SUPPORT THE PURSUIT OF NEW THERAPEUTIC MODALITIES AND MOLECULAR TARGETS. ADULT HIPPOCAMPAL NEUROGENESIS (AHN) HAS LONG BEEN APPRECIATED AS CRITICAL FOR NORMAL LEARNING AND MEMORY IN RODENTS, HOWEVER ITS ROLE IN HUMANS HAS HISTORICALLY BEEN LESS CLEAR. SEVERAL PRECLINICAL STUDIES HAVE UNDERSCORED THE ROLE OF AHN IN IMPROVING COGNITION IN AN AD ENVIRONMENT. CRITICALLY, SEVERAL RECENT STUDIES HAVE SUPPORTED THAT AHN IS ALSO ROBUST IN HUMANS AND PERSISTS THROUGHOUT LIFE IN HEALTHY ADULTS, BUT DECLINES DRAMATICALLY IN AD PATIENTS. THUS, RESTORING AHN HAS EMERGED AS AN ATTRACTIVE TARGET FOR EARLY INTERVENTION, AMELIORATING OR DELAYING THE ONSET OF AD SYMPTOMS. IN THE PROPOSED EXPERIMENTS, BOLDEN THERAPEUTICS WILL DEVELOP THERAPEUTIC MONOCLONAL ANTIBODIES (MABS) THAT REDUCE BONE MORPHOGENETIC PROTEIN (BMP) SIGNALING IN NEURAL STEM CELLS IN VIVO TO INCREASE AHN VIA TARGETING A NOVEL BMP CO-RECEPTOR. BMP SIGNALING IS AN IMPORTANT NEGATIVE REGULATOR OF ADULT NEUROGENESIS, AND INCREASES BOTH IN NORMAL AGING AND IN AD. INHIBITING BMP SIGNALING HAS BEEN SHOWN TO INCREASE NEUROGENESIS, AND THAT IS THE EXPECTED OUTCOME OF OUR PROJECT. THE MABS WILL BE GENERATED BY IMMUNIZING PROPRIETARY, KNOCK- IN MICE, WHICH ARE EXPECTED TO HAVE A MORE ROBUST IMMUNOLOGICAL RESPONSE AND WILL OVERCOME TOLERANCE. THE MOST PROMISING MAB CANDIDATE WILL BE ADMINISTERED USING BOTH DIRECT HIPPOCAMPAL STEREOTACTIC INJECTION AND SYSTEMIC DELIVERY IN AD MICE TO PROVIDE PROOF OF CONCEPT DATA FOR AUGMENTING AHN IN THE SETTING OF DISEASE PATHOLOGY. THESE STUDIES WILL SUPPORT FUTURE PHASE II STUDIES FOR FURTHER CHARACTERIZATION OF THE MAB, INCLUDING EVALUATING ITS EFFECT ON NOT ONLY NEUROGENESIS, BUT ALSO COGNITION AND ADDITIONAL PATHOLOGICAL HALLMARKS (E.G., AMYLOID, TAU, INFLAMMATION). ULTIMATELY, OUR GOAL IS THAT THESE STUDIES WILL ENABLE BOLDEN TO GENERATE THE REQUISITE DATA PACKAGE TO BEGIN CLINICAL DEVELOPMENT OF A PRO-NEUROGENIC THERAPEUTIC ANTIBODY FOR IMPROVING THE CLINICAL COURSE IN MCI/AD, AS WELL AS POTENTIALLY IN OTHER NEUROLOGICAL INDICATIONS.