TY - JOUR
T1 - Allopregnanolone as regenerative therapeutic for Alzheimer's disease
T2 - Translational development and clinical promise
AU - Irwin, Ronald W.
AU - Brinton, Roberta Diaz
N1 - Funding Information:
The work that led to this Review was supported by grants from the NIH National Institute on Aging ( U01 AG031115 ), the Alzheimer Drug Discovery Foundation , the Kenneth T. and Eileen L. Norris Foundation , and The California Institute for Regenerative Medicine ( DR2-05410 ) to R. D. Brinton. The invaluable contributions of M. Rogawski and G. Bauer of the University of California at Davis; J. Wang of the University of Mississippi, and S. Chen of the University of Southern California to our discovery and translational research endeavors described herein are gratefully acknowledged. We extend special gratitude to K. Steinmetz of SRI, International for her contributions to our preclinical toxicology development efforts.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Neurogenesis
KW - Neurosteroid
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Regenerative medicine
KW - Treatment regimen
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U2 - 10.1016/j.pneurobio.2013.08.004
DO - 10.1016/j.pneurobio.2013.08.004
M3 - Review article
C2 - 24044981
AN - SCOPUS:84892885865
SN - 0301-0082
VL - 113
SP - 40
EP - 55
JO - Progress in Neurobiology
JF - Progress in Neurobiology
ER -