ARA-290 10mg

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. [16] 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]

Discovery and design rationale

ARA-290 was rationally designed in the mid-2000s after Brines and Cerami’s laboratory mapped the surface of the EPO molecule and identified that the helix-B aqueous-face residues were responsible for tissue-protective signaling, distinct from the receptor-dimerization face responsible for erythropoiesis. The eleven-residue pyroglutamate-capped sequence was selected to mimic the helix-B surface conformation while maintaining proteolytic stability suitable for systemic research administration in animal models. [2]

Research framework

Within the tissue-protective and innate-repair peptide research domain, ARA-290 is most directly compared with BPC-157 (gastric pentadecapeptide investigated for endothelial NO crosstalk and angiogenic repair), thymosin alpha-1 (TLR-modulating immunopeptide), and TB-500 (G-actin sequestering tissue-repair fragment). These cross-comparisons inform research designs interrogating whether non-hematopoietic EPO-mimetic signaling converges with, or operates independently of, classical actin/cytoskeletal and growth-factor repair pathways. [4]

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 (on the order of minutes), 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 (30–60 µg/kg, p < 0.001 vs vehicle) coupled with suppression of spinal microglia activation. [7]

In the NERVARA trial (n=38, 28 days), corneal nerve fiber area, SFNSL symptom score and 6-Minute Walk Test endpoints were reported. [4]

🩺 Type 2 Diabetes & Metabolic Control

In a Phase 2 study (28 days) in study subjects with type 2 diabetes and neuropathy, HbA1c, lipid-profile and PainDetect endpoints were reported. [5]

In preclinical models, ARA-290 (30 µg/kg) 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, 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 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 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 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): 4-week design; SFNSL and SF-36 physical-functioning endpoints reported. [6]
• NERVARA Trial (n=38): 28-day design; corneal nerve fiber area, SFNSL and 6MWT endpoints reported. [4]
• T2D Neuropathy (n=48): 28-day design; HbA1c, PainDetect and corneal nerve fiber density endpoints reported. [5]
• Diabetic Macular Edema (Phase 2): 12-week design; retinal-thickness, tear-production and metabolic endpoints reported. [10]

Regulatory Status

FDA: Investigational compound. Orphan compound + Fast Track designation for sarcoidosis-associated neuropathy. [16]

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 repeat exposure. No increase in hematocrit, hemoglobin, or platelet counts. Preclinical toxicology showed no adverse effects even at high multiples of active concentrations. [5]