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

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2020-04

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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.

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10.1007/s13311-020-00858-x

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James, Michael L, Jordan M Komisarow, Haichen Wang and Daniel T Laskowitz (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

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.

Komisarow

Jordan Komisarow

Assistant Professor of Neurosurgery
Wang

Haichen Wang

Assistant Professor in Neurology

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