Discovery of a Master Regulator of Injury and Healing: Tipping the Outcome from Damage toward Repair
Disease processes provoke a balancing act between tissue damage and repair. In the 1980s, the discovery that tumor necrosis factor (TNF)-α is a general mediator of disease-related injury led to the development of novel therapeutics to neutralize its activity. In contrast, identification of potential mediator(s) of tissue repair remained elusive. Studies performed over the last 15 years have documented that the type 1 cytokine erythropoietin (EPO), produced by cells within surrounding regions subjected to injury, acts as a master regulator, controlling both damage and repair. The transducer of these activities is the previously unrecognized innate repair receptor (IRR), which is comprised of the EPO receptor and β common receptor subunits. Notably, although proinflammatory cytokines upregulate the IRR, EPO and proinflammatory cytokines inhibit each other’s production, resulting in a relative underproduction of EPO. Although exogenous EPO attenuates disease activity in many preclinical models, its clinical utility is limited by serious hematopoietic and thrombotic adverse effects. To circumvent this problem, novel compounds engineered from the structure of EPO have been developed as selective ligands of the IRR. These compounds possess no hematopoietic activity, yet are fully tissue-protective and reparative. The lead molecule of this development effort (the 11-amino acid peptide ARA290) tips the balance toward healing in diverse preclinical models of disease and is currently under evaluation in advanced clinical trials as a disease-modifying agent in painful neuropathy and diabetes.
As can easily be observed by looking at the publications arising from this area of research over the years, I have been especially blessed by an abundance of collaborators of the highest caliber from around the world. Unfortunately, there are too many to mention here in the concern that I will inadvertently fail to acknowledge someone. It has always amazed me how many individuals take considerable time to meet and discuss topics that are often somewhat outside of their area of core expertise. Without this collegiate collaboration, this work could not have progressed as rapidly or as far as it has. I also sincerely thank the many volunteers and patients, as well as their families, for agreeing to participate in our clinical research programs.
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