ARA-290

What it is

ARA-290 is an 11-amino acid linear non-hematopoietic peptide engineered from the three-dimensional structure of helix B of erythropoietin (EPO) (PMID 36085231, PMID 20). It selectively binds and activates the innate repair receptor (IRR), a heteromeric complex composed of the EPO receptor (EPOR) and the β-common receptor (CD131/βcR), which mediates tissue protection and repair (PMID 25728128, PMID 20). This receptor complex is distinct from the EPOR homodimer that mediates erythropoiesis; consequently, ARA-290 does not stimulate red blood cell production or cause hematopoietic side effects (PMID 20, PMID 36085231). Downstream signaling involves JAK2, PI3K-AKT, and NF-κB pathways (PMID 29026145, PMID 34041477). The IRR is typically not expressed by normal tissues but is rapidly induced by injury or inflammation. ARA-290 has demonstrated anti-inflammatory, anti-apoptotic, antioxidant, and tissue-protective effects across multiple cell types and organ systems (PMID 36085231, PMID 32335150, PMID 25728128). Its plasma half-life has been described as approximately 2 minutes, yet it activates a molecular switch that triggers sustained biological effects. ARA-290 has also been shown to directly inhibit TRPV1 channel activity, providing a mechanism for peripheral analgesic effects independent of IRR.

Class: Non-hematopoietic erythropoietin-derived peptide; innate repair receptor (IRR) agonist

What it's studied for

• Small fiber neuropathy (SFN) in sarcoidosis — neuropathic pain and nerve fiber regeneration Human RCT
  • Randomized, double-blind pilot study in 22 sarcoidosis patients with SFN symptoms. ARA 290 (2 mg IV, three times/week for 4 weeks) significantly improved small fiber neuropathy screening list (SFNSL) score vs. placebo at week 4 (Δ -11.5 ± 3.04 vs. Δ -2.9 ± 3.34; p<0.05). Pain and physical functioning dimensions of SF-3 PMID 23168581 Heij et al., Molecular Medicine 2012
  • Blinded, placebo-controlled trial of 28-day daily subcutaneous ARA 290 in sarcoidosis patients with documented SNFLD. Significant improvement in neuropathic symptoms, significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and increased exercise capacity (6-minute walk t PMID 24136731 Dahan et al., Molecular Medicine 2013
  • Phase 2b, 28-day RCT of 64 subjects with sarcoid-associated SNFL and neuropathic pain. Cibinetide 4 mg/day produced significant placebo-corrected increase in corneal nerve fiber area (CNFA) at day 28 (697 µm², 95% CI 159–1236; P=0.012). Intraepidermal GAP-43+ fibers increased in the 4 mg group (P=0.035). Pain improved PMID 28475703 Culver et al., Investigative Ophthalmology & Visual Science 2017
  • Review of two Phase II clinical trials: ARA 290 treatment consistently associated with significant improvement in neuropathic pain, increased corneal nerve fibers, improved sensory pain thresholds, improved quality of life, and physical functioning. Excellent safety profile reported. PMID 24555851 van Velzen et al., Expert Opinion on Investigational Drugs 2014
• Type 2 diabetes — metabolic control and diabetic neuropathy Human RCT
  • Phase 2 controlled clinical trial. ARA 290 (4 mg) or placebo self-administered subcutaneously daily for 28 days. No safety issues identified. ARA 290 improved HbA1c and lipid profiles over 56-day observation period. PainDetect neuropathic symptoms significantly improved. Subjects with mean CNFD >1 SD below normal showe PMID 25387363 Brines et al., Molecular Medicine 2015
• Diabetic macular edema (DME) Human observational
  • Phase 2 trial, 9 patients, cibinetide 4 mg/day subcutaneously for 12 weeks. No improvement in mean BCVA or CRT. Improvement observed in NEI VFQ-25 composite scores (2.7 ± 3.1). Some participants experienced improvements in CRT, tear production, diabetic control, and albuminuria. No serious adverse events or anti-cibine PMID 32674280 Lois et al., Journal of Clinical Medicine 2020
• Sarcoidosis-associated fatigue Human RCT
  • Systematic review identified ARA 290 among six interventions evaluated for sarcoidosis-associated fatigue. Evidence assessed but risk of bias noted in multiple studies; trial evidence for ARA 290 in fatigue was considered limited. PMID 27507833 Atkins & Wilson, Chronic Respiratory Disease 2017
• Neuropathic pain (preclinical — allodynia, neuritis, spared nerve injury models) Animal studies only
  • ARA290 (3, 10, 30, 60 µg/kg) administered on days 1, 3, 6, 8, and 10 after spared nerve injury in rats dose-dependently reduced mechanical and cold allodynia up to 20 weeks vs. vehicle. 30 µg/kg suppressed spinal microglia reactivity. PMID 24529189 Swartjes et al., Molecular Pain 2014
  • ARA290 (30 or 120 µg/kg IP daily from day 1 post-surgery) prevented development of mechanical allodynia in the rat neuritis model. No significant effect on heat hyperalgesia. Mechanisms did not appear to involve inhibition of TNF-α or CCL2 production. PMID 23262243 Pulman et al., Neuroscience 2013
  • ARA290 demonstrated potential benefits in reducing pain behavior in a rat neuritis model (inflammatory pain). PMID 23456872 Dilley, Methods in Molecular Biology 2013
• Renal ischemia/reperfusion injury and kidney transplantation (preclinical) Animal studies only
  • ARA290 (IV at 0, 2, 4, and 6 hours post-reperfusion) increased glomerular filtration rate over 7-day observation, tended to reduce MCP-1 and IL-6 at 15 min post-reperfusion, and reduced interstitial fibrosis at 7 days in a porcine renal I/R model. PMID 23302512 van Rijt et al., Journal of Translational Medicine 2013
  • Early ARA290 treatment (1 hour post-reperfusion) improved renal function and reduced renal inflammation and acute kidney injury at 3 days in a rat unilateral renal I/R model. Late or repetitive treatment was less effective. PMID 24225194 van Rijt et al., Journal of Translational Medicine 2013
• Cisplatin-induced nephrotoxicity (cytoprotection, in vitro) In vitro only
  • ARA290 (50–400 nM) in HEK-293 and ACHN cells reduced cisplatin-induced DNA damage, oxidative stress (MDA/ROS), pro-inflammatory cytokines (TNFα, IL-6, IL-1β), and apoptosis (caspase-3, Bax); increased Bcl2 expression. PMID 36085231 Ghassemi-Barghi et al., Inflammation 2023
• Doxorubicin-induced genotoxicity and oxidative stress (in vitro cytoprotection) In vitro only
  • ARA290 (50–400 nM) in HepG2, HGF, and stem cell lines significantly reduced DOX-induced DNA damage (micronucleus, comet assay), oxidative stress, inflammation, and apoptotic cell death. PMID 32335150 Shokrzadeh et al., Toxicology In Vitro 2020
• Pancreatic islet transplantation — islet protection and engraftment improvement (preclinical and ex vivo human) Mixed
  • ARA 290 (120 µg/kg IP) perioperatively and at 0, 6, 24 h after transplantation significantly improved blood glucose levels vs. controls in marginal syngeneic PITx in diabetic mice. Protected islets from cytokine-induced apoptosis and inhibited macrophage cytokine secretion in vitro. PMID 26683514 Watanabe et al., Transplantation 2016
  • Cibinetide protected isolated human islets from pro-inflammatory cytokine-induced damage (maintained ATP, reduced caspase 3/7 activity), reduced IBMIR-induced platelet consumption, and improved engraftment of human islets in athymic mice with increased human insulin in livers and reduced CD11b+ infiltration. PMID 34498509 Yao et al., Cell Transplantation 2021
  • Cibinetide (120 µg/kg) perioperatively then daily for 14 days ameliorated local inflammatory responses, improved glycemic control immediately after allogeneic PITx, and significantly delayed allograft loss. Combination with low-dose tacrolimus significantly improved long-term graft survival. PMID 32345869 Yao et al., Transplantation 2020
• Alzheimer's disease — amyloid-β pathology and cognitive function (preclinical) Animal studies only
  • Early systemic ARA 290 administration in young APP/PS1 mice decelerated Aβ pathology progression and improved cognitive functions by increasing Ly6C-low patrolling monocytes. Effects were compromised in aged APP/PS1 mice with advanced AD-like pathology. PMID 34343617 Al-Onaizi et al., Brain Behavior and Immunity 2022
• Cardiac aging, inflammation, and healthspan (preclinical) Animal studies only
  • Chronic ARA290 treatment in 18-month-old Fischer 344 x Brown Norway rats over 15 months mitigated age-related cardiac inflammation (leukocytes, monocytes, NF-κB, pro-inflammatory cytokines), enhanced cardiomyocyte autophagy, desensitized mitochondrial permeability transition pore, blunted age-associated blood pressure PMID 36741836 Winicki et al., Frontiers in Cardiovascular Medicine 2022
• Experimental autoimmune encephalomyelitis / multiple sclerosis (preclinical) Animal studies only
  • ARA290 (35, 70 µg/kg IP once daily from day 7–18 or 9–19) significantly reduced EAE clinical severity and duration in Lewis rats, reduced inflammatory cell accumulation in spinal cord, suppressed pro-inflammatory cytokine mRNA, and shifted T cell polarization toward Th2/Treg. PMID 24518674 Chen et al., Journal of Neuroimmunology 2014
• Experimental autoimmune neuritis / peripheral demyelinating disease (preclinical) Animal studies only
  • ARA 290 intervention in EAN rats improved recovery, nerve regeneration, and remyelination; suppressed nerve inflammation; increased Foxp3+/CD4+ Treg and Th2 cells; decreased Th1 cells; promoted Schwann cell proliferation without inducing hematopoiesis. PMID 24603865 Liu et al., PLoS One 2014
• Systemic lupus erythematosus (preclinical) Animal studies only
  • ARA290 administration in pristane-induced SLE and MRL/lpr mice suppressed antinuclear autoantibodies, reduced IgG/C3 deposition, ameliorated nephritis, reduced serum IL-6, MCP-1, TNF-α, decreased renal apoptosis, inhibited macrophage inflammatory activation, and promoted phagocytosis of apoptotic cells without inducing PMID 29570934 Huang et al., Journal of Cellular and Molecular Medicine 2018
• Cerebral ischemic stroke (preclinical) Animal studies only
  • ARA290 exerted neuroprotective effect in MCAO mouse model similar to EPO, reducing neuronal apoptosis and inflammatory cytokines in brain tissue. Neuroprotective effect was significantly suppressed by siRNA against βCR, confirming βCR-dependence. ARA290 did not cause erythropoiesis. PMID 38488446 Wang et al., CNS Neuroscience & Therapeutics 2024
• Hemolytic-uremic syndrome (preclinical) Animal studies only
  • Administration of pHBSP (ARA-290) to Stx-induced HUS mice improved 7-day survival and attenuated renal oxidative stress. pHBSP attenuated renal nitrosative stress and reduced tubular dedifferentiation, without thromboembolic complications or other adverse side effects. PMID 36211426 Dennhardt et al., Frontiers in Immunology 2022
• Diabetic wound healing (preclinical) Animal studies only
  • Cibinetide (30 µg/kg/day SC) in db/db diabetic mice significantly improved wound MAL, VEGF, pAkt, peNOS, nitrite/nitrate, re-epithelialization, angiogenesis, and wound breaking strength vs. vehicle. PMID 29223734 Bitto et al., BBA Molecular Basis of Disease 2018
  • ARA290-ELP fusion protein accelerated full-thickness diabetic wound healing by increasing angiogenesis. Co-delivery with KGF-ELP (1:4 ratio) produced fastest healing rate, thicker granulation tissue, and regenerated epidermis at 28 days. PMID 28688286 Devalliere et al., Biomaterials 2017
• Ischemic retinopathy / retinal vascular repair (preclinical) Animal studies only
  • Systemic ARA290 (cibinetide) delivered to OIR mice reduced pro-inflammatory IL-1β and TNF-α in retina. Following intravitreal ECFC transplantation, vasoreparative function of ECFCs was significantly enhanced in presence of ARA290 vs. EPO. ARA290 activated pro-survival signaling in ECFCs in vitro. PMID 30876881 O'Leary et al., Experimental Eye Research 2019
• Critical limb ischemia — apoptosis and inflammation in ischemic myotubes (in vitro) In vitro only
  • ARA 290 in C2C12 ischemic myotubes in vitro significantly decreased apoptotic cells (71.1% vs. 55.1%), cleaved caspase-3, LDH release, and IL-6 release compared to ischemia alone. PMID 24055514 Joshi et al., Journal of Vascular Surgery 2014
• Angiogenesis and endothelial progenitor cell function in peripheral ischemia (preclinical) Animal studies only
  • ARA290 enhanced ECFC proliferation, migration, and resistance to H2O2-induced apoptosis in vitro. Single ARA290 injection after ECFC transplantation enhanced hindlimb blood flow ratio and capillary density at 28 days in chronic hindlimb ischemia mice, and improved ECFC homing to ischemic tissue via CD31-dependent mecha PMID 27172159 Hache et al., Shock 2016
• Inflammatory bowel disease / colitis (preclinical) Animal studies only
  • Cibinetide treatment of established DSS-induced colitis in C57BL/6N mice improved weight gain and survival, preserved tissue integrity, reduced myeloid cell infiltration and pro-inflammatory mediators. Anti-inflammatory effects were dependent on CD131 and JAK2 and mediated via inhibition of NF-κB subunit p65. PMID 29026145 Nairz et al., Scientific Reports 2017
• Insulin resistance / metabolic syndrome (preclinical) Animal studies only
  • pHBSP (ARA-290; 30 µg/kg SC) for 11 weeks in mice on high-fat high-sucrose diet ameliorated insulin resistance, reduced hepatic lipid deposition, normalized serum glucose and lipid profiles, improved renal function, attenuated IL-6 and FGF-21, and enhanced mitochondrial biogenesis in skeletal muscle. Note: this publica PMID 25164531 Collino et al., British Journal of Pharmacology 2014
• Bone metabolism — osteoclastogenesis inhibition (preclinical) Animal studies only
  • One month of cibinetide treatment significantly increased cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J female mice. CIB inhibited osteoclastogenesis in vitro and reduced osteoclast progenitor numbers in vivo. PMID 35008482 Awida et al., International Journal of Molecular Sciences 2021
• Mild traumatic brain injury (preclinical) Animal studies only
  • pHBSP (30 µg/kg IP every 12 h for 3 days) starting 1 h or 24 h after mTBI in rats significantly improved Morris water maze performance and reduced CD68+ inflammatory cell activation in brain tissue. PMID 22827443 Robertson et al., Journal of Neurotrauma 2013
• Preeclampsia — endothelial dysfunction (preclinical) Animal studies only
  • pHBSP (ARA-290) at 10 µg/kg and 250 µg/kg corrected L-NAME-induced preeclampsia in Wistar rats. At 250 µg/kg: systolic and diastolic BP decreased ~31–33%, endothelial dysfunction coefficient decreased 48.6%, placental microcirculation increased 82.8%, proteinuria decreased 76.1%. PMID 32942669 Korokin et al., International Journal of Molecular Sciences 2020
• Type 2 diabetes-associated executive cognitive dysfunction (preclinical) Animal studies only
  • ARA 290 improved insulin sensitivity and altered circulating monocyte proportions in db/db mice but did not rescue deficits in executive cognitive flexibility (reversal learning). Improvement in peripheral metabolic function was insufficient to restore executive cognition. PMID 41933665 Alasousi et al., Neurobiology of Disease 2026
• Antidepressant / emotional processing effects (human, healthy volunteers) Human RCT
  • Healthy participants (N=36) received ARA290 (2 mg) or placebo in a double-blind RCT. ARA290 modulated some aspects of emotional processing (lower neural responses to happy faces, faster categorization of positive vs. negative words, increased attention toward positive emotional pictures) but effects did not unequivocal PMID 26431906 Cerit et al., European Neuropsychopharmacology 2015
• Cardiac imaging / SPECT tracer (radiolabeled ARA-290 derivative) Animal studies only
  • 99mTc-DOTA-(Lys-Dabcyl,Phe)-ARA-290 synthesized and radiolabeled with >96% purity. Binding to hypoxic H9c2 cells was 3× higher than normoxic cells at 1 h. Biodistribution and SPECT imaging in cardiac ischemic rat model showed considerable accumulation in ischemic region (ischemic-to-lung ratio 3.65 ID/g% at 0.5 h). PMID 35317117 Mohtavinejad et al., Iranian Journal of Basic Medical Sciences 2021
• Renal allograft injury (preclinical) Animal studies only
  • ARA290 treatment in a rat renal allograft model significantly lowered serum creatinine and BUN, improved renal morphology, decreased macrophage infiltration, reduced NF-κB DNA binding affinity, and downregulated mRNA expression of NF-κB downstream inflammatory mediators (MCP-1, RANTES, ICAM-1, VCAM-1) vs. UW group. PMID 29880388 Yan et al., Transplantation Proceedings 2018
• TRPV1-mediated nociception / pain modulation (in vitro and animal) Mixed
  • ARA 290 specifically inhibited TRPV1 channel activity in HEK293 cells (calcium imaging) and relieved capsaicin-induced mechanical hypersensitivity in mice, suggesting a novel peripheral analgesic mechanism independent of IRR. PMID 26774587 Zhang et al., Peptides 2016