Ara-290
A non-erythropoietic peptide derived from erythropoietin (EPO) that activates the innate repair receptor (IRR) for tissue protection and nerve regeneration. Engineered to retain EPO's powerful tissue-protective signaling while completely eliminating its red blood cell-stimulating effects. Particularly promising for neurological injuries and ischemic tissue damage.
Typical Dosage
Clinical trials: 2-8 mg intravenous or subcutaneous. Despite the ultra-short half-life, the tissue-protective signaling cascades activated persist for hours to days after administration.
Administration
Subcutaneous or intravenous injection
Mechanism of Action
Ara-290 is an 11-amino-acid peptide designed to selectively activate the innate repair receptor (IRR), a heteromeric receptor complex composed of the erythropoietin receptor (EPOR) and the beta common receptor (CD131/βcR). This receptor is distinct from the classical homodimeric EPOR that mediates erythropoiesis, which is why Ara-290 can deliver tissue-protective effects without stimulating red blood cell production or the thrombotic risks associated with EPO.
The IRR is expressed on tissues subjected to metabolic stress, inflammation, or injury — including neurons, Schwann cells, cardiomyocytes, renal tubular cells, and endothelial cells. When Ara-290 activates the IRR, it triggers a cascade of protective signaling pathways: JAK2/STAT5 activation promotes anti-apoptotic gene expression (Bcl-2, Bcl-xL); PI3K/Akt signaling provides cell survival signals; NF-κB modulation shifts the inflammatory balance from pro-inflammatory to pro-resolution. The net effect is protection of viable cells from death, reduction of inflammation, and activation of repair processes.
Ara-290's most clinically advanced application is in peripheral neuropathy, particularly diabetic small fiber neuropathy. Schwann cells — the myelinating glial cells of the peripheral nervous system — express the IRR, and Ara-290 stimulates their survival and regenerative capacity. In clinical trials, subcutaneous Ara-290 administration improved corneal nerve fiber density (a measure of small fiber regeneration) and reduced neuropathic symptoms. Despite its extremely short plasma half-life (approximately 2 minutes), the tissue-protective effects persist for days because the cellular signaling cascades activated by IRR engagement have sustained downstream effects that outlast the peptide's presence in circulation.
Regulatory Status
Not FDA approved. Phase 2 clinical trials completed for diabetic neuropathy and sarcoidosis. Developed by Araim Pharmaceuticals.
Risks & Safety
Common: injection site reactions, mild headache. Serious: still investigational with limited long-term safety data. Rare: allergic reactions. Notably absent: no erythropoietic effects, no thrombotic risk, no blood pressure elevation (unlike EPO). Well tolerated in completed clinical trials. Not FDA approved.
Research Papers
1Published: January 22, 2025
Abstract
Traumatic brain injury (TBI) unfolds through a well-defined chronology-hyperacute excitotoxic and inflammasome bursts, acute apoptotic and blood-brain-barrier failure, and subacute neurovascular remodeling-that no single-pathway drug can adequately cover. Recombinant erythropoietin (EPO) limits secondary damage in animals, yet its erythropoietic drive and thrombotic liability have stalled clinical adoption. This review integrates structural biology, pharmacology and translational data on four engineered EPO derivatives-carbamylated EPO, asialo-EPO, darbepoetin alfa and the helix-B surface peptide (HBSP/cibinetide)-that decouple cytoprotection from red-cell stimulation. We first outline how specific modifications (carbamylation, desialylation, hyper-glycosylation or helix truncation) bias EPOR signaling toward PI3K-AKT and away from JAK2-STAT5. We then match each derivative to its optimal injury window. Meta-analyses of randomized trials suggest a possible trend toward lower short-term mortality without a consistent functional benefit or thrombotic signal. By integrating molecular mechanisms, experimental findings, and early clinical observations, this review outlines hypotheses and future trial frameworks for phase-targeted, erythropoietin-based neuroprotection. Further controlled studies are required to establish safety, efficacy, and optimal therapeutic timing before translation to routine clinical use.
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