ARA 290

ARA 290, also known as Cibinetide, is a synthetic linear peptide consisting of 11 amino acids engineered to mimic the tissue-protective properties of erythropoietin (EPO) without its erythropoietic (blood-forming) effects. While EPO is primarily known for stimulating red blood cell production through the classical EPO receptor (EPOR), it was discovered that EPO also provides profound tissue protection and repair through a separate receptor complex called the innate repair receptor (IRR), a heteromer of EPOR and the beta common receptor (βcR/CD131). ARA 290 was rationally designed by Anthony Cerami and colleagues at Araim Pharmaceuticals to selectively activate the IRR without binding the classical EPOR homodimer, thus capturing EPO's healing benefits without the risks of excessive erythropoiesis (blood clots, stroke). ARA 290 has been studied in multiple clinical trials for diabetic neuropathy (small fiber neuropathy), sarcoidosis, chronic pain syndromes, and metabolic syndrome. It has demonstrated the ability to regenerate small nerve fibers, reduce neuroinflammation, improve metabolic parameters, and promote tissue repair. The peptide represents a novel approach; applying the body's innate repair pathways activated by stress signals to promote healing across multiple tissue types.

ARA 290 selectively activates the innate repair receptor (IRR), a heteromeric receptor complex composed of the erythropoietin receptor (EPOR) and the beta common receptor (βcR/CD131). This receptor is expressed on damaged or stressed tissues and is upregulated by injury, inflammation, and metabolic stress, meaning ARA 290 preferentially acts on tissues that need repair. IRR activation triggers the JAK2/STAT3 signaling pathway, which drives anti-apoptotic gene expression (including Bcl-xL and XIAP), anti-inflammatory cytokine production, and tissue-protective cascades. In neurons, IRR activation promotes small nerve fiber regeneration by stimulating Schwann cell survival, axonal sprouting, and remyelination. ARA 290 suppresses NF-κB-mediated inflammation in macrophages, shifting them from pro-inflammatory (M1) to anti-inflammatory/reparative (M2) phenotypes. In metabolic tissue, IRR signaling improves insulin sensitivity and reduces hepatic steatosis through modulation of inflammatory pathways in adipose tissue and liver. A key feature of ARA 290's mechanism is its tissue-selective action — the IRR is only expressed (or upregulated) in damaged/stressed tissues, so ARA 290 concentrates its effects where repair is needed rather than acting systemically. The extremely short half-life (~2 minutes) paradoxically supports its mechanism, as brief receptor activation is sufficient to trigger sustained downstream repair cascades lasting days.