Therapeutic Development of Apolipoprotein E Mimetics for Acute Brain Injury: Augmenting Endogenous Responses to Reduce Secondary Injury.
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 articleSubject
AnimalsHumans
Brain Diseases
Apolipoproteins E
Neuroprotective Agents
Drug Discovery
Neuroprotection
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https://hdl.handle.net/10161/25394Published Version (Please cite this version)
10.1007/s13311-020-00858-xPublication 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Michael Lucas James
Professor of Anesthesiology
With a clinical background in neuroanesthesia and neurointensive care, I have a special
interest in translational research in intracerebral hemorrhage and traumatic brain
injury. I am fortunate to be part of a unique team of highly motivated and productive
individuals who allow me to propel ideas from bench to bedside and the ability to
reverse translate ideas from the bedside back to the bench.
Jordan Komisarow
Assistant Professor of Neurosurgery
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
Haichen Wang
Assistant Professor in Neurology
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