Ara 290
ARA-290 (cibinetide) is a synthetic 11-amino acid peptide derived from the non-hematopoietic tissue-protective region of erythropoietin that selectively activates the innate repair receptor (EPOR/CD131). It is studied for neuroprotective, anti-inflammatory, and tissue-reparative properties without stimulating erythropoiesis.
ARA-290 (cibinetide) is a synthetic 11-amino acid peptide engineered from the three-dimensional structure of the tissue-protective domain of erythropoietin (EPO). Unlike full-length EPO, ARA-290 selectively engages the heterodimeric innate repair receptor (IRR) composed of EPOR and CD131 (beta common receptor), activating cytoprotective and anti-inflammatory signaling without hematopoietic effects.
Overview
ARA-290 was developed based on the discovery that EPO's tissue-protective effects are mediated through a receptor complex distinct from the classical homodimeric EPOR responsible for erythropoiesis. The innate repair receptor (IRR), a heterodimer of EPOR and CD131, is expressed on neurons, endothelial cells, immune cells, and other tissue types, and is upregulated in response to injury and inflammation. ARA-290 was rationally designed to engage this receptor selectively, retaining EPO's cytoprotective properties while avoiding the risks of polycythemia and thrombosis associated with chronic EPO administration.
The peptide has advanced further into clinical development than most research peptides, with multiple Phase 2 clinical trials completed. Its short plasma half-life (~2 minutes) is offset by prolonged downstream signaling effects, a characteristic shared with other innate repair receptor agonists.
Mechanism of Action
ARA-290 binds to the innate repair receptor (IRR), a heterodimer composed of EPOR and the beta common receptor CD131. This receptor is distinct from the classical homodimeric EPOR that drives erythropoiesis. Upon binding, ARA-290 activates several intracellular signaling cascades:
- JAK2/STAT5 pathway -- Activation of Janus kinase 2 and signal transducer and activator of transcription 5, promoting expression of anti-apoptotic and anti-inflammatory genes.
- PI3K/Akt pathway -- Phosphoinositide 3-kinase/Akt signaling promotes cell survival and suppresses pro-apoptotic factors.
- NF-kB suppression -- Downstream signaling reduces NF-kB-driven inflammatory cytokine production, including TNF-alpha, IL-6, and IL-1beta.
- Anti-inflammatory macrophage polarization -- ARA-290 promotes shift from pro-inflammatory M1 to reparative M2 macrophage phenotypes.
The net effect is tissue protection, reduced inflammation, and promotion of repair processes without stimulating red blood cell production.
Reconstitution Calculator
Ara 290
**ARA-290** (cibinetide) is a synthetic 11-amino acid peptide engineered from th
Exceeds syringe capacity
Dose requires 2.000mL but syringe holds 1mL. Increase BAC water, use a larger syringe, or split injections.
Set up a clean workspace with all supplies ready.
Research
Neuropathic Pain
A key clinical milestone was the Phase 2 trial by Dahan et al. (2013) demonstrating that ARA-290 reduced neuropathic pain symptoms in patients with sarcoidosis-associated small fiber neuropathy. This randomized, placebo-controlled study showed that subcutaneous ARA-290 improved neuropathic pain scores and corneal nerve fiber density, providing the first clinical evidence for IRR-targeted therapy in neuropathic conditions.
Small Fiber Neuropathy in Sarcoidosis
Sarcoidosis-associated small fiber neuropathy (SFN) has emerged as a primary clinical indication for ARA-290. Studies have demonstrated improvements in intraepidermal nerve fiber density and patient-reported pain outcomes. The mechanism is believed to involve both direct neuroprotection via IRR activation on Schwann cells and sensory neurons, and indirect effects through suppression of the inflammatory milieu driving nerve damage.
Metabolic and Vascular Effects
Preclinical studies have examined ARA-290's effects on endothelial progenitor cell mobilization and vascular repair. In diabetic wound models, IRR activation promoted angiogenesis and accelerated tissue healing. These findings connect to the broader role of the innate repair receptor system in coordinating tissue recovery across multiple organ systems.
Tissue Protection and Anti-Inflammation
The foundational work by Brines et al. (2008) demonstrated that small peptides derived from EPO's tissue-protective domain, including ARA-290, could activate the IRR and provide cytoprotection in models of ischemia, inflammation, and neuronal injury without hematopoietic activity. This established the principle that EPO's tissue-protective and erythropoietic functions could be pharmacologically separated.
Brines et al. (2012) further characterized ARA-290 in preclinical models, showing anti-inflammatory effects in metabolic and wound-healing contexts. The peptide reduced inflammatory cytokine levels, promoted tissue repair, and improved metabolic endpoints in diabetic models.
Safety Profile
ARA-290 has been generally well-tolerated in clinical trials. Its short plasma half-life minimizes systemic exposure, and the selective engagement of the IRR (rather than the classical EPOR) avoids erythropoietic stimulation and associated thrombotic risks. Reported adverse effects in Phase 2 trials have been mild, primarily consisting of injection site reactions. Importantly, ARA-290 does not raise hemoglobin levels or hematocrit, differentiating it from EPO and its analogs. Ongoing safety monitoring continues in clinical development programs.
Pharmacokinetic Profile
Ara 290 — Pharmacokinetic Curve
Subcutaneous, intravenous (research/clinical trials)Quick Start
- Typical Dose
- 4 mg daily
- Frequency
- Once daily
- Route
- Subcutaneous, intravenous (research/clinical trials)
- Cycle Length
- 28 days
- Storage
- Lyophilized: 2-8°C refrigerated, protect from light. Reconstituted: use immediately or refrigerate up to 24 hours
Molecular Structure
- Formula
- C50H82N14O22
- Weight
- 1 Da
- Length
- 11 amino acids
- CAS
- 1208243-50-8
- PubChem CID
- 56845983
- Exact Mass
- 165.0460 Da
- LogP
- -3
- TPSA
- 74.8 Ų
- H-Bond Donors
- 2
- H-Bond Acceptors
- 4
- Rotatable Bonds
- 2
- Complexity
- 193
Identifiers (SMILES, InChI)
InChI=1S/C5H11NO3S/c7-10(8,9)4-5-2-1-3-6-5/h5-6H,1-4H2,(H,7,8,9)/t5-/m1/s1
JYFHRLOWRFUNPU-RXMQYKEDSA-NResearch Indications
Neuroprotection
23% increase in corneal nerve fiber area with sustained pain improvement.
Nerve regeneration and metabolic improvements in Type 2 diabetes patients.
Crosses blood-brain barrier for stroke and TBI neuroprotection.
Tissue Repair
Improves epithelialization and angiogenesis via VEGF upregulation.
Reduces infarct size in myocardial infarction models.
Maintains cardiac function in aging models.
Anti-Inflammatory
Reduces TNF-α, IL-6, and IL-12 production.
Reduces colitis severity in animal models.
Improves graft survival and reduces rejection.
Research Protocols
subcutaneous Injection
EPO-derived innervate repair peptide. Simple 2-phase protocol.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Tolerance phase | 2 mg | Once daily | Week 1 |
| Standard dose | 4 mg | Once daily | Weeks 2-8+(No additional benefit at 8 mg. Cycle 4-8 weeks, extendable to 16.) |
Reconstitution Guide (16mg vial + 2mL BAC water)
- Wipe vial tops with alcohol swab
- Draw 2.0 mL bacteriostatic water into syringe
- Inject slowly down the inside wall of the peptide vial
- Gently swirl to dissolve — never shake
- Resulting concentration: 8 mg/mL
- For 2 mg dose: draw 25 units (0.25 mL)
- For 4 mg dose: draw 50 units (0.50 mL)
- Store reconstituted vial refrigerated at 2-8°C
Interactions
Peptide Interactions
Complementary tissue repair pathways may enhance wound healing.
Combined mechanisms enhance recovery from injury.
No known interactions; different mechanisms for tissue protection.
No adverse interactions in clinical trials with GLP-1 agonists.
Clinical trials exclude EPO use within 2 months due to receptor interference.
What to Expect
What to Expect
Initial anti-inflammatory effects and mild pain symptom improvement
Progressive nerve regeneration, improved tissue healing markers
Peak therapeutic effects, maximum nerve fiber density improvements
Long-lasting benefits via molecular switch effect
Safety Profile
Common Side Effects
- Excellent safety profile in clinical trials with no serious drug-related adverse events
Contraindications
- Recent anti-TNF therapy (within 6 months)
- EPO use (within 2 months)
- Pregnancy
- BMI > 34 kg/m²
Discontinue If
- Severe injection site reactions
- Unexpected blood count changes
- Allergic reaction signs
- Worsening of underlying condition
- New neurological symptoms
- Any serious adverse events
Quality Indicators
What to look for
- Pharmaceutical grade manufacturing with GMP conditions
- Proper peptide sequence verification - correct 11-amino acid sequence with N-terminal pyroglutamate
- Sterile lyophilized powder with proper freeze-drying
- Clinical batch documentation - Purity >95%, endotoxin <1 EU/mg, sterility verified
Caution
- Light-sensitive formulation - requires protection during storage and use
Red flags
- Cloudy or discolored solution indicates degradation; should be clear to slightly cloudy
Frequently Asked Questions
References (10)
- [2]
- [1]Sarcoidosis Neuropathy Phase 2b Trial (2017)
- [4]Myocardial Infarction Protection Study (2012)
- [5]Stroke Neuroprotection Research (2011)
- [9]Dahan, A. et al Cibinetide for the treatment of sarcoidosis-associated small fiber neuropathy Expert Opin Investig Drugs (2023)
- [10]Brines, M. & Bhatt, D.L Tissue-protective peptides: bridging the gap between innate repair and clinical application Mol Med (2022)
- [6]Brines, M. et al Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin Proc Natl Acad Sci USA (2008)
- [3]
- [7]
- [8]
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