What is ARA 290?


Jan 18, 2023
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What is ARA 290?

ARA 290 is a non-erythropoietic peptide engineered from erythropoietin (EPO), a hormone that stimulates the production of red blood cells. It is a modified version of the naturally occurring hormone, which has been found to have a neuroprotective effect. ARA 290 has been shown to have several potential therapeutic uses in a variety of neurological conditions.

Research studies have shown that ARA 290 has the ability to cross the blood-brain barrier and reach the central nervous system (CNS).

This ability allows ARA 290 to act on cells in the brain and spinal cord and has led to the investigation of its potential therapeutic effects in various diseases of the CNS. Studies in animal models of Alzheimer's disease and traumatic brain injury have shown that ARA 290 has the ability to improve cognitive function, reduce brain damage and inflammation. In addition to its potential therapeutic effects, ARA 290 has been found to have a number of beneficial effects on neural cells, including the promotion of neurogenesis, or the growth of new neurons, and the protection of neurons from damage.

How does ARA 290 work?
ARA 290 is a selective antagonist of the A2A receptor, which is a subtype of the adenosine receptors. These receptors are G protein-coupled receptors (GPCRs) that are widely expressed in the brain and are involved in a variety of physiological functions such as the regulation of blood flow, neurotransmitter release, and neuronal excitability. The A2A receptors are known to play a critical role in regulating dopamine levels, particularly in the striatum, a brain region that is involved in motor control and reward-related behaviors.

The mechanism of action of ARA 290 is believed to involve the blockade of the A2A receptors in the striatum, which leads to an increase in dopamine levels and an improvement in dopamine-mediated functions such as movement and motivation. In addition, it is thought that ARA 290 may also have modulatory effects on other neurotransmitters such as glutamate and GABA.

In preclinical studies, ARA 290 has shown efficacy in improving motor symptoms in animal models of Parkinson's disease and ameliorating cognitive and negative symptoms in animal models of schizophrenia.

Based on the literature, ARA 290 has been shown to target:

• Parkinson’s disease - ARA 290 is being studied as an adjunctive treatment to levodopa, the current gold standard treatment for Parkinson's disease. It is thought that ARA 290 may help to improve the motor symptoms of Parkinson's disease by increasing dopamine levels in the striatum.

• Schizophrenia - ARA 290 is being studied as a potential treatment for cognitive and negative symptoms. Cognitive symptoms include difficulties with memory, attention, and decision making, while negative symptoms include apathy, lack of motivation, and social withdrawal. It is thought that ARA 290 may improve these symptoms by modulating the activity of neurotransmitters such as dopamine and glutamate.

• Neuropathy - ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. Studies have shown a benefit in both metabolic control and neuropathy in subjects with type 2 diabetes.

Research Example 1:

Erythropoietin and derivatives: Potential beneficial effects on the brain

Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non-hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression. Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.

Research Example 2:

Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action

Studies on the neural effects of Erythropoietin (EPO) indicate that EPO may have antidepressant effects. Due to its hematopoietic effects, EPO may cause serious side-effects with repeated administration if patients are not monitored extensively. ARA290 is an EPO-analog peptide without such hematopoietic side-effects but may have neurotrophic and antidepressant effects. The aim of this study was to investigate the possible antidepressant effects of ARA290 in a neuropsychological model of drug action.

Healthy participants (N=36) received ARA290 (2 mg) or placebo in a double-blind, randomized, parallel-group design. Neural and cognitive effects were assessed one week after administration. Primary outcome measures were the neural processing of fearful vs happy faces and the behavioral recognition of emotional facial expressions.

ARA290-treated individuals displayed lower neural responses to happy faces in the fusiform gyrus. ARA290 tended to lower the recognition of happy and disgusted facial expressions. Although ARA290 was not associated with a better memory for positive words, it was associated with faster categorization of positive vs negative words. Finally, ARA290 increased attention towards positive emotional pictures. No effects were observed on mood and affective symptoms.

ARA290 may modulate some aspects of emotional processing, however, the direction and the strength of its effects do not unequivocally support an antidepressant-like profile for ARA290. Future studies may investigate the effects of different timing and dose.

Research Example 3:

The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain

Introduction: Sarcoidosis is a multi-system inflammatory disorder that may affect the peripheral nerves causing neuropathic pain. Chronic neuropathic pain is a debilitating disease and current treatment options are either of limited efficacy or are hampered by the development of serious side effects. A novel pharmacological treatment option is the non-hematopoietic erythropoietin analog ARA 290, a small peptide acting at the innate repair receptor, which is a heteromer of the erythropoietin receptor and β-common receptor. ARA 290 was recently granted designation as Orphan Drug Product by the FDA, for treatment of neuropathic pain in sarcoidosis patients.

Areas covered: This report reviews the pathophysiology of sarcoidosis and, to understand the mechanistic pathway of ARA 290, the role of the innate repair receptor in inflammation and its natural and synthetic ligands, erythropoietin, and ARA 290. The results of two proof-of-concept studies are presented that show the ability of ARA 290 to induce analgesia greater than placebo in patients with sarcoidosis-induced chronic moderate to severe neuropathic pain, without safety issues.

Expert opinion: ARA 290 is a promising novel therapeutic option in the treatment of neuropathic pain in sarcoidosis. Further studies are designed to obtain additional proof of ARA 290's analgesic efficacy and ability to increase the quality of life in afflicted patients.

Research Example 4:

ARA 290, a Non-erythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes

Although erythropoietin ameliorates experimental type 2 diabetes with neuropathy, serious side effects limit its potential clinical use. ARA 290, a nonhematopoietic peptide designed from the structure of erythropoietin, interacts selectively with the innate repair receptor that mediates tissue protection. ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. To evaluate the potential activity of ARA 290 in type 2 diabetes and painful neuropathy, subjects were enrolled in this phase 2 study. ARA 290 (4 mg) or placebo were self-administered subcutaneously daily for 28 d and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Subjects receiving ARA 290 exhibited an improvement in hemoglobin A1c (Hb A1c) and lipid profiles throughout the 56-d observation period. Neuropathic symptoms as assessed by the Pain Detect questionnaire improved significantly in the ARA 290 group. Mean corneal nerve fiber density (CNFD) was reduced significantly compared with normal controls and subjects with a mean CNFD >1 standard deviation from normal showed a significant increase in CNFD compared with no change in the placebo group. These observations suggest that ARA 290 may benefit both metabolic control and neuropathy in subjects with type 2 diabetes and deserves continued clinical evaluation.

In summary, ARA 290 shows significant potential for the treatment of Parkinson’s disease, schizophrenia, and neuropathy. It is also currently being studied for treatment of other neurological diseases and disorders in addition to drug addiction as well