ARA-290

ARA-290 (also known as cibinetide) is a synthetic 11-amino acid peptide derived from the three-dimensional structure of erythropoietin (EPO), specifically modeled after the helix-B surface domain of the EPO molecule. [2] Unlike full-length EPO, ARA-290 is non-hematopoietic — it does not stimulate red blood cell production (erythropoiesis), thereby avoiding the cardiovascular and thrombotic risks associated with EPO experimental protocol such as hypertension and thromboembolic events. [3]

ARA-290 was developed by Araim Pharmaceuticals (Tarrytown, NY), co-founded by Dr. Michael Brines and Dr. Anthony Cerami, to harness the potent tissue-protective and anti-inflammatory properties of EPO without triggering its hematological reported observations in study populations. [18] The peptide selectively activates the Innate Repair Receptor (IRR), a heterocomplex of the EPO receptor (EPOR) and the CD131 beta-common receptor (βcR). The IRR is typically not expressed in healthy tissue but is rapidly upregulated in response to cellular stress, hypoxia, or inflammation. [4]

ARA-290 has received FDA Orphan compound Designation and Fast Track status for the investigation of sarcoidosis-associated neuropathy, and also holds EMA Orphan compound Designation for sarcoidosis. [9] It is currently an investigational compound not registered for experimental use. ARA-290 is not listed on the WADA Prohibited List, although its EPO-related origin could be subject to future review. [6]

1. Primary Receptor Target — The Innate Repair Receptor (IRR)

ARA-290 selectively binds to the Innate Repair Receptor (IRR), a heteromeric complex consisting of the erythropoietin receptor (EPOR) and the CD131 beta-common receptor (βcR). [3] The IRR is normally not expressed in healthy tissues but is rapidly upregulated locally in response to tissue injury, hypoxia, or metabolic stress. [4] Critically, ARA-290 does not bind to the EPOR homodimer responsible for erythropoiesis, confirming its non-hematopoietic selectivity. [2]

Swartjes et al. (2011) confirmed this selectivity by demonstrating that ARA-290 had no analgesic effect in β-common receptor knockout mice (βcR−/−), proving absolute dependence on the CD131 subunit. [3]

2. Downstream Signaling — JAK2 / STAT / PI3K / MAPK

Binding to the IRR initiates phosphorylation of Janus kinase 2 (JAK2), which propagates signal transduction through three principal pathways: [18]

• STAT Pathway: Activates STAT transcription factors to promote anti-apoptotic gene expression.
• PI3K/Akt Pathway: Modulates cell survival, stem cell migration, and regional blood flow for tissue repair.
• MAPK Pathway: Reduces inflammation, edema, and mediates anti-apoptosis.

ARA-290 also significantly inhibits NF-κB nuclear translocation, reducing pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β) and increasing anti-inflammatory IL-10. [1]

3. Anti-Inflammatory and Neuroprotective Effects

In spinal cord tissue following nerve injury, ARA-290 suppresses microglia activation (reduced Iba-1 immunoreactivity) and astrocyte reactivity (reduced GFAP expression), shifting activated macrophages back to a resting phenotype. [7] It also downregulates NMDA receptor subunits (NR1, NR2A, NR2B) and inhibits TRPV1 channel activity, both key modulators of neuropathic pain. [7]

4. Cytoprotection and Mitochondrial Health

ARA-290 desensitizes the mitochondrial permeability transition pore (mPTP) to oxidant stress, significantly elevating the threshold for ROS-induced mPTP opening in cardiomyocytes. [1] Chronic research application enhances autophagy flux and reduces lipofuscin accumulation, key markers of cellular aging. [1]

5. "Molecular Switch" — Short Half-Life, Sustained Effects

Despite a very short plasma half-life (~2 minutes IV, ~20 minutes subcutaneous), ARA-290 triggers a "molecular switch" upon IRR activation. [4] Biological effects — including anti-apoptotic signaling, cytokine suppression, and nerve regeneration — persist long after the peptide has cleared from circulation. Activation requires concentrations exceeding approximately 1 nmol/L (~1.3 ng/mL). [5]

🧠 Neuropathic Pain & Small Fiber Neuropathy (SFN)

ARA-290 has been extensively studied for its ability to relieve neuropathic pain and repair small nerve fibers. In a spared nerve injury model, Swartjes et al. demonstrated a dose-dependent, long-term relief of both mechanical and cold allodynia lasting up to 20 weeks (doses: 30–60 µg/kg IP, p < 0.001 vs vehicle) coupled with suppression of spinal microglia activation. [7]

In human clinical trials (the NERVARA trial), 4 mg SC daily for 28 days produced a 14.5% increase in corneal nerve fiber area vs. a 5.3% decrease in placebo (p = 0.022), demonstrating measurable nerve regeneration. [4] The SFNSL symptom score improved by −12.2 points in the ARA-290 group vs. −3.8 in placebo (p = 0.005), and 6-Minute Walk Test distance increased by +18.7 m vs. −15.1 m in placebo (p = 0.049). [4]

🩺 Type 2 Diabetes & Metabolic Control

In Phase 2 studies involving study subjects with type 2 diabetes, ARA-290 (4 mg SC daily for 28 days) significantly improved HbA1c (−0.16% vs. −0.01% placebo, p = 0.002), with effects sustained at day 56. [5] Lipid profiles including triglycerides and cholesterol/HDL ratio also improved. PainDetect neuropathy scores improved +3.3 points vs. +1.1 in placebo (p = 0.037). [5]

In preclinical models, ARA-290 (30 µg/kg SC) ameliorated diet-induced insulin resistance in mice, reducing hepatic lipid deposition, normalizing serum glucose, and enhancing mitochondrial biogenesis in skeletal muscle. [12]

❤️ Cardiovascular Protection & Aging

Chronic ARA-290 research application (100 µg/kg IP, tri-weekly for 15 months) in aging rats mitigated the age-associated increase in left ventricular end-systolic volume by ~75% (p < 0.05), blunted ejection fraction decline by almost half (p < 0.0001), and significantly reduced blood pressure elevation (p < 0.008). [1] Treated rats showed significantly lower cardiac inflammation (CD45 leukocytes p < 0.001, CD68 monocytes p < 0.001), reduced NF-κB activity, and lower frailty index scores at 33 months of age (p < 0.001). [1]

See also: BPC-157 and TB-500 for related tissue repair research.

Animal Studies

• Neuropathic Pain (Rats): 30–60 µg/kg IP produced dose-dependent, long-term (20-week) relief of mechanical and cold allodynia with suppressed spinal microglia activation. [7]
• Cardiovascular Aging (Rats): 100 µg/kg IP tri-weekly for 15 months preserved cardiac function (ejection fraction, LV volume), reduced cardiac inflammation (NF-κB, CD45, CD68), improved frailty index, enhanced autophagy flux. No significant lifespan extension (p = 0.182). [1]
• Insulin Resistance (Mice): 30 µg/kg SC ameliorated diet-induced metabolic dysfunction, normalized glucose/lipid profiles, enhanced mitochondrial biogenesis. [12]
• Islet Transplantation (Rats): 120 µg/kg/day protected islets from cytokine-induced apoptosis in vitro (75.2% vs. 54.6% viability, p < 0.05). [14]
• Depression (Mice): Daily ARA-290 ameliorated chronic stress-induced depression-like behavior comparable to fluoxetine, reversing microglia activation. [7]
• Wound Healing (Rats): Topical application in diabetic rats accelerated wound closure, reduced re-epithelialization period, and increased collagen content. [17]

Human Clinical Trials

• Sarcoidosis SFN Pilot (n=22): 2 mg IV 3x/week for 4 weeks — SFNSL score improved −11.5 vs. −2.9 in placebo (p < 0.05); improved SF-36 physical functioning. [6]
• NERVARA Trial (n=38): 4 mg SC daily for 28 days — 14.5% increase in corneal nerve fiber area (p = 0.022); SFNSL improved −12.2 vs. −3.8 (p = 0.005); 6MWT improved +18.7 m vs. −15.1 m (p = 0.049). [4]
• T2D Neuropathy (n=48): 4 mg SC daily for 28 days — HbA1c improved −0.16% vs. −0.01% (p = 0.002); PainDetect improved +3.3 vs +1.1 (p = 0.037); CNFD increased +2.6 fibers/mm² in high-risk group (p = 0.02). [5]
• Diabetic Macular Edema (Phase 2): 4 mg SC daily for 12 weeks improved retinal thickness, tear production, and metabolic control. [10]

Regulatory Status

FDA: Investigational compound. Orphan compound + Fast Track designation for sarcoidosis-associated neuropathy. [9]

EMA: Orphan compound Designation for sarcoidosis.

WADA: Not currently on the Prohibited List, but EPO-related origin may be subject to future review.

reported tolerability profile: No anti-ARA-290 antibodies detected after 28 days of daily dosing. No increase in hematocrit, hemoglobin, or platelet counts. Preclinical toxicology showed no adverse effects at doses up to 1000x the initial human dose. [5]