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Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury.

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Date
2020-04
Authors
James, Michael L
Komisarow, Jordan M
Wang, Haichen
Laskowitz, Daniel T
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Abstract
Over the last few decades, increasing evidence demonstrates that the neuroinflammatory response is a double-edged sword. Although overly robust inflammatory responses may exacerbate secondary tissue injury, inflammatory processes are ultimately necessary for recovery. Traditional drug discovery often relies on reductionist approaches to isolate and modulate specific intracellular pathways believed to be involved in disease pathology. However, endogenous brain proteins are often pleiotropic in order to regulate neuroinflammation and recovery mechanisms. Thus, a process of "backward translation" aims to harness the adaptive properties of endogenous proteins to promote earlier and greater recovery after acute brain injury. One such endogenous protein is apolipoprotein E (apoE), the primary apolipoprotein produced in the brain. Robust preclinical and clinical evidence demonstrates that endogenous apoE produced within the brain modulates the neuroinflammatory response of the acutely injured brain. Thus, one innovative approach to improve outcomes following acute brain injury is administration of exogenous apoE-mimetic drugs optimized to cross the blood-brain barrier. In particular, one promising apoE mimetic peptide, CN-105, has demonstrated efficacy across a wide variety of preclinical models of brain injury and safety and feasibility in early-phase clinical trials. Preclinical and clinical evidence for apoE's neuroprotective effects and downregulation of neuroinflammatory and the resulting translational therapeutic development strategy for an apoE-based therapeutic are reviewed.
Type
Journal article
Subject
Animals
Humans
Brain Diseases
Apolipoproteins E
Neuroprotective Agents
Drug Discovery
Neuroprotection
Permalink
https://hdl.handle.net/10161/25394
Published Version (Please cite this version)
10.1007/s13311-020-00858-x
Publication Info
James, Michael L; Komisarow, Jordan M; Wang, Haichen; & Laskowitz, Daniel T (2020). Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 17(2). pp. 475-483. 10.1007/s13311-020-00858-x. Retrieved from https://hdl.handle.net/10161/25394.
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Scholars@Duke

James

Michael Lucas James

Associate Professor of Anesthesiology
I have an extensive background in neuroanesthesia and neurointensive care and a special research interest in translational and clinical research aspects of intracerebral hemorrhage. After completing residencies in neurology and anesthesiology with fellowships in neurocritical care, neuroanesthesia, and vascular neurology, I developed a murine model of intracerebral hemorrhage in the Multidisciplinary Neuroprotection Laboratories at Duke University. After optimization of the model, I h
Komisarow

Jordan Komisarow

Assistant Professor of Neurosurgery
Laskowitz

Daniel Todd Laskowitz

Professor of Neurology
Our laboratory uses molecular biology, cell culture, and animal modeling techniques to examine the CNS response to acute injury. In particular, our laboratory examines the role of microglial activation and the endogenous CNS inflammatory response in exacerbating secondary injury following acute brain insult. Much of the in vitro work in this laboratory is dedicated to elucidating cellular responses to injury with the ultimate goal of exploring new therapeutic interventions in the clinical settin
Wang

Haichen Wang

Assistant Professor in Neurology
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