ApoE Mimetic Peptides as Therapy for Traumatic Brain Injury

Abstract

The lack of targeted therapies for traumatic brain injury (TBI) remains a compelling clinical unmet need. Although knowledge of the pathophysiologic cascades involved in TBI has expanded rapidly, the development of novel pharmacological therapies has remained largely stagnant. Difficulties in creating animal models that recapitulate the different facets of clinical TBI pathology and flaws in the design of clinical trials have contributed to the ongoing failures in neuroprotective drug development. Furthermore, multiple pathophysiological mechanisms initiated early after TBI that progress in the subacute and chronic setting may limit the potential of traditional approaches that target a specific cellular pathway for acute therapeutic intervention. We describe a reverse translational approach that focuses on translating endogenous mechanisms known to influence outcomes after TBI to develop druggable targets. In particular, numerous clinical observations have demonstrated an association between apolipoprotein E (apoE) polymorphism and functional recovery after brain injury. ApoE has been shown to mitigate the response to acute brain injury by exerting immunomodulatory properties that reduce secondary tissue injury as well as protecting neurons from excitotoxicity. CN-105 represents an apoE mimetic peptide that can effectively penetrate the CNS compartment and retains the neuroprotective properties of the intact protein.

Keywords: Drug development; Neurodegeneration; Neuroinflammation; Neuroprotection; Traumatic brain injury.

Fig. 1

Translation vs. reverse translation. The conventional bench to bedside approach for development of therapeutic strategies, known a translation, involves basic science research in the lab, leading to drug development, and culminating in human clinical trials. Alternatively, a bedside to bench approach, known as reverse translation, takes clinical observations and utilizes them to inform the development of new therapies in the laboratory. Considering the slow progress in identifying an effective therapeutic for TBI using traditional methods thus far, reverse translation may augment traditional approaches by helping to identify therapeutic targets and influence trial design

Fig. 2

Figure demonstrating the amino acid structure of the receptor binding face of ApoE with the five peptide residues that comprise CN-105 highlighted in blue. Ala alanine, Arg arginine, Asp Aspartate, His histidine, Leu leucine, Lys lysine, Ser serine, and Val valine (used with permission: Guptill JT, Raja S, Ramey S, et al. Phase I randomized, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects. J Clin Pharmacol. 2017;57(6):770–776)