Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

Abstract

Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and β common receptor (βcR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA-290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide.

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

“…5 Although parallel assessments of lower limb distal IENFD did not show a similar change, quantification of new nerve fiber growth within the epidermis using GAP-43 immunostaining also supported a cibinetide-related increase in small nerve fiber regeneration. This observation is strengthened further by the significant positive correlation noted between changes in CNFA and GAP-43 þ fiber length.…”

“…9 Despite a short plasma half-life, cibinetide triggers sustained biological effects when concentrations exceed the low nanomolar affinity of the receptor. 5 Notably, in a mouse model of diabetic SNFL, daily administration of cibinetide reversed neuronal dystrophy. 7 In neuropathic states the transient receptor potential vanilloid-1 (TRPV1) ion channel, a key integrator of nociception and neurogenic inflammation, undergoes upregulation and sensitization in peripheral small nerve fibers and central pain pathways.…”

“…This system is activated by the innate repair receptor (IRR) comprised of b common (CD131) and erythropoietin receptor subunits, which signals via janus kinase-2 and multiple downstream intracellular molecular pathways. 5 IRR activation promotes tissue protection and repair in a wide variety of preclinical models, 5 including neuropathy. [6][7][8] Cibinetide (ARA 290; helix B surface peptide) is a novel 11 amino acid peptide with high affinity and selectivity for the IRR.…”

The Insect Ortholog of the Human Orphan Cytokine Receptor CRLF3 Is a Neuroprotective Erythropoietin Receptor

“…The nature of the neuroprotective Epo receptor is currently debated. As non-erythropoietic candidate receptors, common β chain receptor/classical EpoR heteromers expressed in the nervous system (Brines and Cerami, 2005; Collino et al, 2015) and bone tissue (Duedal Rölfing et al, 2014) and leukemia inhibitory factor LIFR/DC130 expressed in neuronal and other cell lines (Bonnas, 2012) are discussed. However, even within a particular tissue such as the nervous system, the expression of Epo receptors may depend on cell type, developmental stage, physiological condition and actual as well as previous exposure to challenging stimuli (Sinor and Greenberg, 2000; Brines and Cerami, 2005; Shein et al, 2005; Um et al, 2007; Sanchez et al, 2009).…”

An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

“…The addition of ARA 290 significantly suppressed caspase 3/7 activity after co-culturing with proinflammatory cytokines compared to the vehicle-treated control group. Mechanistically, ARA 290 exerts anti-inflammatory, antiapoptotic, and tissue-protective effects through its interaction with the IRR [35][36][37] and subsequently suppresses the nuclear factor-κB-driven gene transcription of pro-inflammatory mediators, which leads to the phosphorylation of endothelial nitric oxide synthase and other signaling systems [35,38,39]. Exposure of proinflammatory cytokines causes IRR expression on the cell surface [24] and therefore the addition of ARA 290 could activate this receptor to prevent cytokine-induced damage and apoptosis.…”