The long-range goal of our therapeutic development endeavors is to develop efficacious and safe agents to prevent and/or delay progression of age-related neurodegenerative disease such as Alzheimer's. Toward that end, we propose a preclinical project to develop the neurosteroid, allopregnanolone as a neurogenic regenerative therapeutic. The current proposal is a translational therapeutic development project to conduct preclinical analyses required for an Investigational New Drug (IND) application to the FDA to determine the efficacy of allopregnanolone as a neurogenic regenerative agent. Preclinical IND studies proposed herein build upon our foundation of basic science discovery and mechanistic understanding of allopregnanolone action in neural progenitor cells. To conduct the proposed project, we have assembled an interdisciplinary team of scientists with expertise in 1) neurobiology of allopregnanolone (Brinton USC research team), 2) behavioral analyses to determine therapeutic efficacy on learning and memory functions affected in mild cognitive impairment and Alzheimer's disease (PsychoGenics), and 3) pharmacokinetics, pharmacodynamics, toxicology, therapeutic formulation, regulatory affairs and IND document preparation (Stanford Research Institute International;SRI) 4). In addition, we have assembled a team of Consultants with expertise in development of therapeutics for AD within the following domains: 1) AD therapeutic development within the pharmaceutical industry, 2) regulatory affairs, 3) pharmacokinetics and dynamics, 4) therapeutic formulation, 5) design of clinical trials and 6) cognitive and neurological deficits diagnostic of mild cognitive impairment and AD. Consistent with preclinical analyses required for an FDA IND application, we propose four IND related Specific Aims and one project management Specific Aim. Together these aims are designed to [I] Determine therapeutic efficacy of allopregnanolone and impact of age and gender on efficacy in the triple transgenic mouse model of Alzheimer's;[II] Determine pharmacodynamics, pharmacokinetics (ADME) and toxicology of allopregnanolone;[III] Acquire cGMP quality allopreganaolone for Phase I Clinical Trial;[IV] Generation of FDA Investigational New Drug Application and Clinical Investigator Brochure documents;and [V] Project Management to achieve IND filing goal.
Each Specific Aim i s designed to address preclinical IND requirements and each is milestone driven with clearly articulated Go / no-Go decision criteria.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAG1-ZIJ-3 (O3))
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Buckholtz, Neil
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University of Southern California
Schools of Pharmacy
Los Angeles
United States
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PLOS ONE Staff (2015) Correction: Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer's Disease. PLoS One 10:e0132210
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Irwin, Ronald W; Solinsky, Christine M; Brinton, Roberta Diaz (2014) Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. Front Cell Neurosci 8:203
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