Therapeutics to prevent, delay and treat Alzheimer's disease (AD) remains to be achieved. Currently, over 5 million Americans are diagnosed with AD and the number is projected to increase to 11-16 million within two decades unless therapeutic advances are made. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce AD pathology. Allopregnanolone (Allo) is a pleiotropic regenerative therapeutic that promotes neurogenesis and restores cognitive function in both a preclinical AD model and wild type aged mice and reduces pathology in a preclinical AD model. Further Allo promotes regeneration of human neural stem cells. Allo is a neurosteroid endogenous to the brain of low molecular weight and blood brain barrier penetrant with abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation and restoration of cognitive function are well characterized and consistent with well-described neurogenic mechanisms in brain. Allo reduces AD pathology via well-established pathways upstream to Abeta generation to prevent the generation of Abeta while also decreasing inflammation and increasing myelin generation. Based on a foundation of preclinical discovery (ADDF), translational research (NIA U01), clinical development with NIA USC ADRC and FDA assessment, we propose a Phase 1 multiple ascending dose clinical trial of four Allo doses administered in a regenerative regimen of once-per-week for twelve weeks to establish a safe and tolerated dose of Allo necessary to advance to a Phase 2 efficacy trial. To achieve this goal, two specific aims are proposed.
Aim 1 is designed to conduct a Phase 1 multiple ascending dose trial of Allo in participants diagnosed with MCI due to AD and early AD. Primary safety objectives are to determine: 1) maximally tolerated dose;2) incidence and severity of treatment emergent adverse events;3) designated medical events;4) clinically important changes in safety assessments including amyloid related imaging abnormalities (ARIA).
Aim 2 is designed to conduct exploratory safety and feasibility analyses regarding the effect of once- per-week-exposure for 12 weeks to Allo at 4 doses on cognitive function and MRI-based biomarkers. Secondary objectives are to: 1) assess potential short-term effects of Allo dosing on cognition and MRI indicators of AD;2) inform subsequent phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy. A multidisciplinary team of investigators with expertise in Allo systems biology and translational research and clinical trials for AD therapeutics are committed to the project. Trial outcomes will provide: 1) an estimated safe and well-tolerated dose of Allo;2) parameter estimates for cognitive efficacy to advance to a Phase 2 proof of concept trial of Allo;and 3) parameter estimates for MRI-based biomarkers. This proposal meets the objectives of RFA-AG-13-016.

Public Health Relevance

This project addresses the urgent need to develop therapeutics to prevent, delay and treat Alzheimer's disease (AD) in those at greatest risk, the aged. A promising regenerative medicine approach is to activate the brain's endogenous regenerative ability while also reducing the pathology of AD. We propose here to conduct a Phase 1 clinical study of the neurosteroid allopregnanolone (Allo) which promotes the generation of new neurons, restores cognitive function, reduces AD pathology and regenerates white matter in brain.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Cooperative Agreement (UF1)
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Special Emphasis Panel (ZAG1-ZIJ-1 (A2))
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Ryan, Laurie M
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University of Southern California
Schools of Pharmacy
Los Angeles
United States
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