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.