ARA 290 Peptide: From Erythropoietin for Neuropathic Symptoms

A non-hematopoietic peptide called ARA 290, designed based on erythropoietin's structure, can preferentially connect with the innate repair receptor responsible for performing tissue protection. It has been demonstrated that ARA 290 administration is effective in preclinical and clinical investigations on metabolic control and neuropathic symptoms.

EPO derivative structure of ARA 290 from study

The linear peptide ARA 290 has a molecular weight of 1257 Daltons and consists of 11 amino acids. Pyr is an abbreviation for pyroglutamic acid, and the sequence of amino acids is as follows: Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser. The figure that follows provides an illustration of the chemical structure of ARA 290.

Standard toxicity studies conducted on animals demonstrated no adverse responses observed in dosages that were up to one thousand times the starting human dose of one microgram per kilogram (Araim Pharmaceuticals, Inc.,[1]). Additionally, no safety concerns were found in healthy volunteers who were administered supra-clinical dosages and in neuropathic symptoms in patients who received therapeutic dosages and had end-stage renal disease, diabetes, or sarcoidosis. [1].

Development background

Because of its natural function as a powerful anti-inflammatory cytokine, erythropoietin (EPO) has been explored as a possible treatment for cardiovascular disease. Nevertheless, the primary erythropoietic consequences of direct EPO therapy, which include an increase in the mass of red blood cells and, as a consequence, an increased risk of thromboembolic outcomes, were found to be more detrimental than the potential therapeutic benefits of this treatment. [2]. Consequently, the creation of ARA 290 (cibinetide) began.

This peptide is generated from the tissue's protective region of erythropoietin but does not possess any erythropoietic properties. By a heterodimeric receptor consisting of EPOR and CD131, the β common chemokine receptor ARA 290 plays a role in tissue protection by lowering inflammatory and fibrotic responses. This is accomplished by the formation of receptor complexes with the α receptor parts that are specific for GM-CSF, IL-3, and IL-5. [3]

 Michael Brines stated that the 11-amino acid peptide ARA 290, which is the lead component of his development study, is now being evaluated across advanced studies as a disease-modifying drug in painful neurotoxicity and diabetes. It has been shown to tilt the balance toward healing in a variety of preclinical models of disease. [4]

Tissue protective properties

ARA 290 is a synthetic peptide that is generated from the tertiary structure of erythropoietin (EPO), which is a hormone that is primarily recognized for its function in the production of red blood cells. To make use of the tissue-protective and healing capabilities of EPO without promoting erythropoiesis, this cutting-edge peptide has been developed.

Studies conducted in both preclinical and clinical settings have demonstrated that ARA 290 possesses great promise in its capacity to reduce inflammatory processes, promote recovery, and protect various organs and tissues from injury.

Mechanism of Action of ARA 290 Peptide EPO Receptor Binding during Neuropathic Pain

EPO receptor binding

Erythropoietin's structure served as the inspiration for the creation of ARA 290. It accomplishes this by specifically engaging with the innate repair receptor, which is responsible for this tissue protection. Apoptosis, also known as programmed cell death, and inflammation are both reduced as a result of this, which in turn drives tissue healing.

Inflammatory pathways

The actions of ARA 290 are achieved by the selective activation of the innate repair receptor (IRR), which is a heteromeric complex consisting of EPO receptor (EPOR) and β common receptor (βcR) subunits. Because of this particular contact, a chain reaction of signaling events is triggered, which ultimately results in actions that are anti-inflammatory, tissue-protective, and repair-promoting.

To modify the immune response, it has been demonstrated that ARA 290 can reduce the production of cytokines that promote inflammation while simultaneously raising the expression of mediators that inhibit inflammation. In addition to this, it helps numerous cell types, such as endothelial cells, heart muscle cells, and neurons, to survive and function properly when they are subjected to stressful conditions.

Neuroprotective effects

ARA 290 was found to diminish allodynia in a dose-dependent manner, which was accompanied by a reduction of the spinal microglia response. This finding suggests that there is a mechanistic connection between the inhibition of central inflammation that ARA 290 induces and the alleviation of neuropathic pain symptoms. [6].

Research Evidence

• ARA-290 was able to restore tissue homeostasis in mice cells by regulating signaling pathways that are associated with inflammation. Because persistent inflammation can cause damage to tissues and contribute to a variety of disorders, its regulation is especially important because of its potential health implications. The potential of ARA 290 to restore equilibrium in pro-inflammatory signaling pathways implies that it may be beneficial for disorders that involve the central nervous system, which is a region of the body in which inflammation frequently plays a significant role. [7]

• When applied to a model of retinal ischemia, which is characterized by an inadequate supply of blood to the eye, ARA 290 was able to prolong cell life and improve blood vessel repair. According to these findings, ARA 290 has the potential to be an effective therapeutic agent for the treatment of retinal illnesses that include ischemia. A pilot study that is conducted with a double-masked design would be necessary in order to evaluate its efficacy and safety further. In individuals who are suffering from retinal ischemia, a study of this nature might be beneficial in determining the best dosage and evaluating the therapeutic advantages of ARA 290 [8].

• By inhibiting the production of spinal inflammatory mediators like CCL2, ARA 290 inhibited the development of neuropathic pain in rats that had suffered a spinal cord injury. These findings suggest that it has the ability to reduce inflammation in the spinal cord and alleviate the pain feelings that are linked with it. [9].

• By decreasing the levels of the inflammatory chemical TNF-α, ARA 290 was able to alleviate neuropathic pain in a mouse model where it was administered. Given this information, it appears that ARA 290 may have a considerable anti-inflammatory effect, which is one of the factors that contribute to its pain-relieving qualities. In addition, the fact that some cells have the capacity to alleviate neuropathic pain further demonstrates the potential of cell treatments in the management of illnesses that cause chronic pain [10].

Applications of ARA-290 peptide

• Neuroprotection: ARA 290 has been shown to have neuroprotective qualities in studies of spinal cord injury, brain injury due to trauma, and ischemic stroke. These properties include the reduction of neuronal damage and the promotion of functional recovery. 

• Cardioprotection: Studies have demonstrated that ARA 290 can protect the heart against ischemia-reperfusion injury, decrease the size of the infarct, and enhance cardiac function in experimental models of myocardial infarction.

• Protection of the kidneys: In preclinical studies of acute kidney damage and chronic renal failure, it has been discovered that ARA 290 can reduce the severity of renal damage and enhance kidney function. 

• Anti-inflammatory effects: ARA 290 may possess powerful anti-inflammatory capabilities, including reducing the generation of cytokines that promote inflammation and promoting the resolution of inflammation in various tissues. 

• In animal models of cutaneous, corneal, and intestinal injuries, it has been demonstrated that ARA 290 has the ability to hasten the healing process of wounds and accelerate the regeneration of damaged tissue in diabetic neuropathy cases. 

• Several clinical investigations have shown that ARA 290 administration is capable of effectively improving metabolic control and neuropathic symptoms in patients who suffer from sarcoidosis and symptoms in patients with type 2 diabetes mellitus. 

Future Research Perspectives on Neuropathy

Rhabdomyolysis-induced acute renal injury was prevented in mice by administration of ARA 290, which showed protective effects. Based on this information, it appears that ARA 290 treatment may play a role in maintaining renal function in situations where muscle breakdown is occurring. The potential therapeutic implications of this substance in the treatment of kidney injury should be better understood by additional studies into its tertiary structure and mode of action.

For the purpose of determining how receiving ARA 290 interacts with targets within cells and improving its pharmacological characteristics, it is essential to have a solid understanding of its tertiary structure. In order to facilitate the development of ARA 290 as a medicinal agent, the characterization of its tertiary structure may provide insights into its reliability, bioavailability, and mechanism of action.

In addition, analyzing the tertiary structure of ARA 290 can be of assistance in the development of analogs that have enhanced particularity and efficacy. It is crucial to investigate the tertiary structure of ARA 290 in order to evaluate its stability under physiological settings and to make predictions regarding its pharmacokinetic features. By decoding the tertiary structure of ARA 290, we may discover new binding sites and interaction partners, which will allow us to gain a deeper comprehension of the biological roles of this protein.[11].

Early clinical trials testing ARA 290 for nerve regeneration have shown encouraging results. Some studies were able to demonstrate improvements in sensory function, pain alleviation, and overall quality of life in individuals who were suffering from neuropathic pain.

On the other hand, more studies are required to determine the appropriate dosage, treatment time frame, and long-term effects of ARA 290 therapy on neuron regeneration in human beings. The continuation of the study into the mechanisms that underlie the neuroprotective and regenerative qualities of ARA 290 might pave the way for the development of new methods to treat nerve injuries and neuropathy illnesses.

When it comes to the study of corneal nerve fiber and neuropathic pain processes with the evaluation of prospective treatment strategies, the sparing nerve injury (SNI) model has proven to be very helpful. Through the use of the SNI model, a study has been conducted that has yielded significant insights into the effectiveness of ARA 290 in reducing neuropathic pain and facilitating nerve healing.

According to these findings, the ARA 290 group has the potential to be an effective therapeutic agent for the treatment of neuropathic pain that is caused by spinal cord injuries.

 References 

1.     Niesters, M., et al., The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Expert Opinion on Orphan Drugs, 2013. 1(1): p. 77-87.

2.     Brines, M. et al., Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proceedings of the National Academy of Sciences, 2008. 105(31): p. 10925-10930.

3.     Winicki, N.M., et al., A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age-associated declines in heart function and prolongs healthspan. Frontiers in Cardiovascular Medicine, 2023. 9: p. 1096887.

4.     Brines, M., Discovery of a master regulator of injury and healing: tipping the outcome from damage toward repair. Molecular medicine, 2014. 20: p. S10-S16.

5.     Pulman, K.G., et al., The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model. Neuroscience, 2013. 233: p. 174-183.

6.     Swartjes, M., et al., ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Molecular pain, 2014. 10: p. 1744-8069-10-13.

7.     Bohr, S., et al., Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells. Journal of Molecular Medicine, 2015. 93: p. 199-210.

8.     O'Leary, O.E., et al., The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic. Experimental Eye Research, 2019. 182: p. 144-155.

9.     Swartjes, M., et al., Ketamine does not produce relief of neuropathic pain in mice lacking the β-common receptor (CD131). PLoS One, 2013. 8(8): p. e71326.

10.   Takahashi, T., et al., The effect of ketamine anesthesia on the immune function of mice with postoperative septicemia. Anesthesia & Analgesia, 2010. 111(4): p. 1051-1058.

11.   Wang, S., et al., Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization. Cell death & disease, 2017. 8(4): p. e2725-e2725.