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- W2765926265 abstract "Alzheimer's disease (AD) is a national and global epidemic with complex pathoetiology including compromised brain metabolic activity and decreased regenerative capacity. Allopregnanolone (Allo) is an investigational neuroregenerative therapeutic, currently in Phase 1b clinical trial for AD (NCT02221622, https://clinicaltrials.gov/ct2/show/NCT02221622?term=NCT02221622&rank=1). In rodent preclinical models, Allo promotes neural stem cell (NSC) proliferation and neural differentiation and improves mitochondrial function. To develop biomarkers to predict regenerative response to Allo, we have initiated proof of concept analyses to determine the impact of Allo on human induced pluripotent stem cells (iPSCs) and iPSC-derived neural cells. T-cells from Allo clinical trial participants were reprogrammed via a non-integrating, non-viral method, to iPSCs. Additional iPSCs were provided by the University of California Irvine Alzheimer's Disease Research Center (UCI-ADRC) and the Institute for Memory Impairments and Neurological Disorders. Using dual inhibition of SMAD signaling, iPSCs were differentiated to NSCs. Mitochondrial respiration and regenerative capacity were determined by metabolic analyzer and FACS. Analyses were conducted to determine the regenerative and bioenergetic effect of Allo on clinical trial participant iPS-derived NSCs. Within the cell lines of the first cohort of participants, after Allo treatment, 40% had increased NSC proliferation (mean increase 14% versus vehicle) and also bioenergetic capacity (mean increase 13% versus vehicle). These participant cell lines have been labeled ‘responders’, while those that did not have increased NSC proliferation or metabolic capacity are ‘non-responders’. These data demonstrate that Allo promotes regeneration and mitochondrial function of iPSC-derived NSCs in a subset of clinical trial participants. In order to translate these in vitro data to be clinically relevant, the next step is to analyze this cell data for correlations with the clinical trial cognitive and imaging data. These data form the foundation for developing the first biomarker of regenerative potential in brain to determine and monitor response to allopregnanolone as a regenerative therapeutic. Research supported by NIH/NIA U01AG031115 and UF1AG046148 to RDB; NIH/NINDS R00-NS07743 and the Donald E. and Delia B. Baxter Foundation to JKI; NIH/NIA AG005142 to HCC; UCI-ADRC funded by NIH/NIA Grant P50 AG16573; USC Provost Fellowship, CIRM Predoctoral Research Traineeship, and American Foundation for Pharmaceutical Education Fellowship to CMS." @default.
- W2765926265 created "2017-11-10" @default.
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- W2765926265 date "2017-07-01" @default.
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- W2765926265 title "[P3-167]: DEVELOPMENT OF AN IPSC-BASED BIOMARKER STRATEGY TO IDENTIFY NEUROREGENERATIVE RESPONDERS TO ALLOPREGNANOLONE" @default.
- W2765926265 doi "https://doi.org/10.1016/j.jalz.2017.06.1379" @default.
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