ARA-290 Research in Immune Modulation and Neurotherapy

ARA-290

ARA-290 is a peptide derivative of erythropoietin (EPO). Erythropoietin is the primary hormone responsible for erythropoiesis, which is the production of new red blood cells. In addition, it is also involved in angiogenesis (production of new blood vessels), cell survival, blood pressure regulation, and neuroprotection in diabetic neuropathy.

ARA-290 peptide provides only a selective range of nociceptive and neuroprotective effects and evades hemopoietic action. It is of great interest to researchers because of these two properties and their role in wound repair in diabetes and immune modulation in autoimmune diseases. It has cleared phase 2 trials and is currently in phase 3 trials.

RESEARCH IMPLICATIONS OF ARA-290 PEPTIDE:

BLOOD VESSEL INTEGRITY

ARA-290 peptide plays a significant role in prolonging cell survival and helping Endothelial Colony Forming Cells (ECFCs) repair and rebuild blood vessels after their integrity has been compromised following an injury. Similarly, the ARA-290 peptide can protect retinal epithelial cells from ischemic or inflammatory injury, promote repair, and lead to regeneration.

ARA-290 can improve the migration, proliferation, and homing ability of Endothelial Colony Forming Cells, which favors the targeted repair of blood vessels that have undergone damage. Studies have indicated that ARA-290 peptide augments the effect of endogenous ECFCs and the transplanted exogenous ECFCs to repair and establish the vasculature of ischemic tissues.

DOWNREGULATION OF INFLAMMATORY CYTOKINES AND TISSUE PROTECTION

Lately, the surgical management of diabetes has been done by transplantation of viable insulin-producing islet cells to make up for insulin deficiency in people with diabetes. This provided a regulated physiological control of diabetes and prevented long-term grave complications of diabetes. However, this method was soon abandoned because this led to the activation of macrophages, implant rejection, and ultimately implant failure. Studies have demonstrated the potential of the ARA-290 peptide in suppressing this inflammatory cascade by inhibiting the release of TNF-alpha, IL-6, and IL-12, which prolongs the survival of exogenous Islet cells.

The mechanism behind this inflammatory suppression involves the binding of the ARA-290 peptide to the Tissue Protective Receptor (TPR). This reduces harmful inflammatory mediators’ effect, which boosts tissue protection. Erythropoietin does play the above role, but it comes with the cost of its hematopoietic and cardiovascular side effects. ARA-290 peptide leads to better wound healing and quick post-injury recovery, reducing morbidity and mortality.

ROLE OF ARA-290 IN IMMUNE SYSTEM REGULATION

There is mounting evidence that supports the role of ARA-290 peptide in immune modulation through the binding of the ARA-290 to Tissue Protective Receptors, which are expressed by a wide range of immune cells, including lymphocytes, dendritic cells, mast cells, and macrophages.
After binding ARA-290 to the macrophages, it suppresses the release of proinflammatory mediators. This leads to decreased pathogen clearance, but it reduces disease severity and prevents long-term morbidity due to chronic inflammation. It also lessens the release of inflammatory chemokines by the macrophages and reduces inflammatory infiltration while favoring resident macrophage recruitment to the site of injury at the same time. This prevents the side effects of inflammation on the surrounding tissues.

Studies have demonstrated the effect of ARA-290 peptide in altering the antigenic property of dendritic cells to lead to increased long-term resistance against pathogens to which the host has already been exposed. This forms the foundation of its role in preventing tissue, organ, or graft rejection following transplantation.

Research has shown the effect of ARA-290 in reducing the levels of ANA and anti-dsDNA in Systemic Lupus Erythematous (SLE). The two auto-antibodies are considered the markers of disease progression and indicators of diagnosis in SLE. It also saves the kidney from SLE damage, leading to the morbidity associated with SLE. ARA-290 peptide is assumed to become the first-ever targeted treatment for SLE.

ARA-290 IN NOCICEPTION

Neuropathic pain caused by diabetic neuropathy is difficult to control and poorly understood in terms of its underlying pathophysiology. However, research has shown that this can be alleviated by suppressing Innate Repair Receptors (IRR) on which ARA-290 peptide can act. This also inhibits TRPV1 channel (Capsaicin receptor) activity, which is responsible for the perception of burning pain associated with neuropathy.

Small nerve fiber neuropathy associated with several autoimmune diseases, such as sarcoidosis, diabetes, and HIV, leads to the loss of tiny nerve fibers and, ultimately, severe neuropathic burning pain. Studies have shown that treatment with ARA-290 peptide increases these fibers and significantly controls pain.

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