ARA-290, published under the development name cibinetide, is a short peptide modelled on the helix B region of erythropoietin. It exists because of a specific pharmacological observation: the tissue-protective activity attributed to erythropoietin appears to be mediated by a different receptor assembly from the one that drives red blood cell production. This overview covers the receptor pharmacology, the sequence derivation and the published clinical record. Trial outcome statements are reproduced as direct quotations with attribution, and no therapeutic claim is made anywhere here.
Two receptors, two functions
The starting point is the 2008 paper by Brines et al. (2008) in the Proceedings of the National Academy of Sciences. Its abstract states verbatim:
"Erythropoietin (EPO), a member of the type 1 cytokine superfamily, plays a critical hormonal role regulating erythrocyte production as well as a paracrine/autocrine role in which locally produced EPO protects a wide variety of tissues from diverse injuries. Significantly, these functions are mediated by distinct receptors: hematopoiesis via the EPO receptor homodimer and tissue protection via a heterocomplex composed of the EPO receptor and CD131, the beta common receptor. In the present work, we have delimited tissue-protective domains within EPO to short peptide sequences."
Brines M, et al. PNAS 2008;105:10925-10930.
That EPO receptor / CD131 heterocomplex is what the later literature calls the innate repair receptor (IRR). ARA-290 is one of the short sequences produced by that programme: an 11-residue peptide that mimics the solvent-facing surface of helix B, which is not part of the erythropoietin receptor binding face responsible for erythropoiesis. In published rodent and cell culture models the peptide is reported to engage the IRR without stimulating red cell production.
Why a helix-B peptide
Erythropoietin is a four-helix bundle glycoprotein. The residues that bind the erythropoietin receptor homodimer sit on parts of helices A, C and D and on the loop joining helices A and B, while helix B faces the surrounding fluid when the hormone is bound (Brines et al., 2008). The Brines programme reasoned that if tissue protection were signalled through a separate receptor assembly, the structural determinants for it might sit elsewhere on the molecule and could be isolated. Helix B, and specifically its aqueous-facing surface, was the region that retained tissue-protective activity in their models when presented as a short peptide. ARA-290 is a linear synthetic peptide built from the amino acids that form that surface. Those residues sit next to each other in the folded helix rather than in one continuous stretch of the erythropoietin sequence, so the peptide is not a simple excised fragment of the hormone.
Practically, this matters for research design in two ways. First, the peptide is a short linear sequence rather than a glycoprotein, so it is accessible by solid-phase synthesis and is what suppliers such as Peptx list as a lyophilised reference material. Second, because it is reported not to drive erythropoiesis, haematocrit is not the readout used to characterise it, unlike work with erythropoietin itself.
The published clinical programme
Sarcoidosis with small fibre neuropathy (Molecular Medicine, 2012)
The first published clinical report, by Heij et al. (2012), is a randomised, double-blind pilot study run at Leiden University Medical Center. Its abstract states verbatim:
"A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial ... No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo. ... ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms."
Heij L, et al. Molecular Medicine 2012;18(1):1430-1436.
This is an exploratory pilot with 22 participants, and the same abstract reports that Brief Pain Inventory and fatigue scores improved to a similar degree in both the ARA 290 and placebo groups. It is quoted here because it was the first randomised human study of the compound to be published, not as evidence of efficacy at any scale. Dosing details have been left out of the quotation.
Review and later work
Van Velzen et al. (2014) reviewed the sarcoidosis small fibre neuropathy work in Expert Opinion on Investigational Drugs. Dahan et al. (2016) later set out the receptor rationale in a review in Pain Reports titled "Targeting the innate repair receptor to treat neuropathy".
Cibinetide has also been evaluated outside neuropathy. Lois et al. (2020) published a small phase 2 clinical trial of cibinetide in diabetic macular oedema (nine patients) in the Journal of Clinical Medicine, and Yao and colleagues reported islet work in mouse transplant models and isolated human islets: Yao et al. (2020) in Transplantation and Yao et al. (2021) in Cell Transplantation. Those are separate research contexts and their endpoints do not transfer to the neuropathy literature.
Handling notes for laboratory use
ARA-290 is supplied lyophilised in sealed glass vials. As with other short linear peptides, storage of the lyophilised powder at low temperature and protection from moisture and light are the standard considerations described in supplier documentation. Peptx does not publish administration or protocol guidance, and no human dosing figures appear on this page.
Related pages
References
- Brines M, et al. (2008). Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proceedings of the National Academy of Sciences of the United States of America. PubMed 18676614
- Dahan A, et al. (2016). Targeting the innate repair receptor to treat neuropathy. Pain Reports. PubMed 29392190
- Heij L, et al. (2012). Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Molecular Medicine. PubMed 23168581
- Lois N, et al. (2020). A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema. Journal of Clinical Medicine. PubMed 32674280
- van Velzen M, et al. (2014). ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert Opinion on Investigational Drugs. PubMed 24555851
- Yao M, et al. (2020). Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand. Transplantation. PubMed 32345869
- Yao M, et al. (2021). Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation. Cell Transplantation. PubMed 34498509
Research use only. ARA-290 (cibinetide) is not licensed for human use in the UK, EU or US and is supplied by Peptx strictly as laboratory reference material.