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Prog Neurobiol. 2014 Feb;113:40-55. doi: 10.1016/j.pneurobio.2013.08.004. Epub 2013 Sep 14.

Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise.

Author information

1
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
2
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: rbrinton@usc.edu.

Abstract

Herein, we review a translational development plan to advance allopregnanolone to the clinic as a regenerative therapeutic for neurodegenerative diseases, in particular Alzheimer's. Allopregnanolone, an endogenous neurosteroid that declines with age and neurodegenerative disease, was exogenously administered and assessed for safety and efficacy to promote neuro-regeneration, cognitive function and reduction of Alzheimer's pathology. Allopregnanolone-induced neurogenesis correlated with restoration of learning and memory function in a mouse model of Alzheimer's disease and was comparably efficacious in aged normal mice. Critical to success was a dosing and treatment regimen that was consistent with the temporal requirements of systems biology of regeneration in brain. A treatment regimen that adhered to regenerative requirements of brain was also efficacious in reducing Alzheimer's pathology. With an optimized dosing and treatment regimen, chronic allopregnanolone administration promoted neurogenesis, oligodendrogenesis, reduced neuroinflammation and beta-amyloid burden while increasing markers of white matter generation and cholesterol homeostasis. Allopregnanolone meets three of the four drug-like physicochemical properties described by Lipinski's rule that predict the success rate of drugs in development for clinical trials. Pharmacokinetic and pharmacodynamic outcomes, securing GMP material, development of clinically translatable formulations and acquiring regulatory approval are discussed. Investigation of allopregnanolone as a regenerative therapeutic has provided key insights into mechanistic targets for neurogenesis and disease modification, dosing requirements, optimal treatment regimen, route of administration and the appropriate formulation necessary to advance to proof of concept clinical studies to determine efficacy of allopregnanolone as a regenerative and disease modifying therapeutic for Alzheimer's disease.

KEYWORDS:

2-hydroxypropyl β-cyclodextrin; 3-hydroxy-3-methyl-glutaryl-CoA-reductase; 3xTgAD; 3α-HSD; 3α-hydroxysteroid dehydrogenase; 3β-HSD; 3β-hydroxysteroid dehydrogenase; 5α-DHP; 5α-R; 5α-dihydroprogesterone; 5α-reductase; ABAD; AD; ANT; AUC; Allo; Alzheimer's disease; Aβ; CMC; CYP3A; CYP450scc; EMA; European Medicines Agency; FDA; GLP; Good Laboratory Practices; Good Manufacturing Practices; HMG-CoA-R; HβCD; IM; IN; IND; IV; LXR; MED; MTD; Neurogenesis; Neurosteroid; PKA; PKCɛ; PXR; Pharmacodynamics; Pharmacokinetics; Regenerative medicine; SBEβCD; SC; SGZ; SVZ; StAR; TD; TSPO; Treatment regimen; United States Food and Drug Administration; VDAC; adenine nucleotide transporter protein; allopregnanolone; amyloid-beta binding alcohol dehydrogenase; area under the curve; cGMP; chemistry, manufacturing, and controls; cytochrome P450 3A; cytochrome P450 side-chain cleavage; intramuscular; intranasal; intravenous; investigational new drug; liver-X-receptor; maximum tolerated dose; minimal effective dose; non-transgenic; nonTg; pregnane-X-receptor; protein kinase A; protein kinase C epsilon; steroidogenic acute regulatory protein; subcutaneous; subgranular zone; subventricular zone; sulfobutyl ether β-cyclodextrin; transdermal; translocator protein; triple transgenic mouse model of AD; voltage-dependent anion channel protein; β-amyloid

PMID:
24044981
DOI:
10.1016/j.pneurobio.2013.08.004
[Indexed for MEDLINE]

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