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

James, Michael L

Komisarow, Jordan M

Wang, Haichen

Laskowitz, Daniel T

2022-06-21T12:34:32Z

2022-06-21T12:34:32Z

2020-04

2022-06-21T12:34:31Z

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.

10.1007/s13311-020-00858-x

1933-7213

1878-7479

https://hdl.handle.net/10161/25394

eng

Springer Science and Business Media LLC

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

10.1007/s13311-020-00858-x

Animals

Humans

Brain Diseases

Apolipoproteins E

Neuroprotective Agents

Drug Discovery

Neuroprotection

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

Journal article

James, Michael L|0000-0002-8715-5210

Komisarow, Jordan M|0000-0003-3919-7931

Laskowitz, Daniel T|0000-0003-3430-8815

475

483

2

Duke

School of Medicine

Basic Science Departments

Clinical Science Departments

Institutes and Centers

Neurobiology

Anesthesiology

Anesthesiology, Neuroanesthesia

Surgery

Trauma, Acute, and Critical Care Surgery

Duke Clinical Research Institute

Institutes and Provost's Academic Units

University Institutes and Centers

Duke Global Health Institute

Neurology

Neurology, Neurocritical Care

Initiatives

Duke Science & Society

Neurosurgery

Published

17