Introduction:

ARA290 is an amino acid peptide derived from the helix B of erythropoietin (EPO), a hormone involved in the production of red blood cells (Brines & Cerami, 2012). ARA290 is neuroprotective and tissue-protective without causing hematopoietic and thrombotic side effects that are usually seen in patients given exogenous EPO (Brines et al., 2008). Mechanistically, ARA290 acts on the innate repair receptor system and initiates persistent signaling cascades that lead to protective and reparative effects in cells and tissues (Collino et al., 2015). Clinically, it was proven that ARA290 is useful for treating sarcoidosis and ARA290 has received US Orphan Drug and Fast Track designations for treating neuropathic pain associated with sarcoidosis (Dahan et al., 2013). Albeit more studies are needed, ARA290 may also be efficient for treating other neuroinflammatory diseases (Chen et al., 2014; Liu et al., 2014, Robertson et al., 2013) and may be able to modulate cognitive functions (Cerit et al., 2015; Seeger et al., 2011).

Future Research

• Clinical studies on other neuroinflammatory diseases besides sarcoidosis

• Assess the psychiatric effects of ARA290

• Develop an oral form of ARA290

References

Brines, Michael, & Cerami, A. (2012). The receptor that tames the innate immune response. In Molecular medicine (Cambridge, Mass.) (Vol. 18, Issue 1, pp. 486–496). The Feinstein Institute for Medical Research. https://doi.org/10.2119/molmed.2011.00414

Brines, Michael, Patel, N. S. A., Villa, P., Brines, C., Mennini, T., De Paola, M., Erbayraktar, Z., Erbayraktar, S., Sepodes, B., Thiemermann, C., Ghezzi, P., Yamin, M., Hand, C. C., Xie, Q. W., Coleman, T., & Cerami, A. (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, 105(31), 10925–10930. https://doi.org/10.1073/pnas.0805594105

Collino, M., Thiemermann, C., Cerami, A., & Brines, M. (2015). Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacology and Therapeutics, 151, 32–40. https://doi.org/10.1016/j.pharmthera.2015.02.005

Dahan, A., Dunne, A., Swartjes, M., Proto, P. L., Heij, L., Vogels, O., van Velzen, M., Sarton, E., Niesters, M., Tannemaat, M. R., Cerami, A., & Brines, M. (2013). ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Molecular Medicine, 19(1), 334–345. https://doi.org/10.2119/molmed.2013.00122

Chen, H., Luo, B., Yang, X., Xiong, J., Liu, Z., Jiang, M., Shi, R., Yan, C., Wu, Y., & Zhang, Z. (2014). Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat. Journal of Neuroimmunology, 268(1–2), 64–70. https://doi.org/10.1016/j.jneuroim.2014.01.006

Liu, Y., Luo, B., Han, F., Li, X., Xiong, J., Jiang, M., Yang, X., Wu, Y., & Zhang, Z. (2014). Erythropoietin-Derived Nonerythropoietic Peptide Ameliorates Experimental Autoimmune Neuritis by Inflammation Suppression and Tissue Protection. PLoS ONE, 9(3), e90942. https://doi.org/10.1371/journal.pone.0090942

Robertson, C. S., Garcia, R., Gaddam, S. S. K., Grill, R. J., Cerami Hand, C., Tian, T. S., & Hannay, H. J. (2013). Treatment of Mild Traumatic Brain Injury with an Erythropoietin-Mimetic Peptide. Journal of Neurotrauma, 30(9), 765–774. https://doi.org/10.1089/neu.2012.2431

Cerit, H., Veer, I. M., Dahan, A., Niesters, M., Harmer, C. J., Miskowiak, K. W., Rombouts, S. A. R. B., & Van der Does, W. (2015). Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action. European Neuropsychopharmacology, 25(12), 2289–2299. https://doi.org/10.1016/j.euroneuro.2015.09.005

Seeger, N., Zellinger, C., Rode, A., Roloff, F., Bicker, G., Russmann, V., Fischborn, S., Wendt, H., & Potschka, H. (2011). The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model. Epilepsia, 52(12), 2333–2343. https://doi.org/10.1111/j.1528-1167.2011.03302.x 

Brines, M., Patel, N. S. A., Villa, P., Brines, C., Mennini, T., De Paola, M., Erbayraktar, Z., Erbayraktar, S., Sepodes, B., Thiemermann, C., Ghezzi, P., Yamin, M., Hand, C. C., Xie, Q. W., Coleman, T., & Cerami, A. (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, 105(31), 10925–10930. https://doi.org/10.1073/pnas.0805594105

Niesters, M., Swartjes, M., Heij, L., Brines, M., Cerami, A., Dunne, A., HoitsM.A., E., & Dahan, A. (2013). The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Expert Opinion on Orphan Drugs, 1(1), 77–87. https://doi.org/10.1517/21678707.2013.719289

Collino, M., Thiemermann, C., Cerami, A., & Brines, M. (2015). Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacology and Therapeutics, 151, 32–40. https://doi.org/10.1016/j.pharmthera.2015.02.005 

Heij, L., Niesters, M., Swartjes, M., Hoitsma, E., Drent, M., Dunne, A., Grutters, J. C., Vogels, O., Brines, M., Cerami, A., & Dahan, A. (2012). Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study. Molecular Medicine, 18(11), 1430–1436. https://doi.org/10.2119/molmed.2012.00332

Dahan, A., Dunne, A., Swartjes, M., Proto, P. L., Heij, L., Vogels, O., van Velzen, M., Sarton, E., Niesters, M., Tannemaat, M. R., Cerami, A., & Brines, M. (2013). ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Molecular Medicine, 19(1), 334–345. https://doi.org/10.2119/molmed.2013.00122

Chen, H., Luo, B., Yang, X., Xiong, J., Liu, Z., Jiang, M., Shi, R., Yan, C., Wu, Y., & Zhang, Z. (2014). Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat. Journal of Neuroimmunology, 268(1–2), 64–70. https://doi.org/10.1016/j.jneuroim.2014.01.006

Liu, Y., Luo, B., Han, F., Li, X., Xiong, J., Jiang, M., Yang, X., Wu, Y., & Zhang, Z. (2014). Erythropoietin-Derived Nonerythropoietic Peptide Ameliorates Experimental Autoimmune Neuritis by Inflammation Suppression and Tissue Protection. PLoS ONE, 9(3), e90942. https://doi.org/10.1371/journal.pone.0090942

Robertson, C. S., Garcia, R., Gaddam, S. S. K., Grill, R. J., Cerami Hand, C., Tian, T. S., & Hannay, H. J. (2013). Treatment of Mild Traumatic Brain Injury with an Erythropoietin-Mimetic Peptide. Journal of Neurotrauma, 30(9), 765–774. https://doi.org/10.1089/neu.2012.2431

Seeger, N., Zellinger, C., Rode, A., Roloff, F., Bicker, G., Russmann, V., Fischborn, S., Wendt, H., & Potschka, H. (2011). The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model. Epilepsia, 52(12), 2333–2343. https://doi.org/10.1111/j.1528-1167.2011.03302.x

Cerit, H., Veer, I. M., Dahan, A., Niesters, M., Harmer, C. J., Miskowiak, K. W., Rombouts, S. A. R. B., & Van der Does, W. (2015). Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action. European Neuropsychopharmacology, 25(12), 2289–2299. https://doi.org/10.1016/j.euroneuro.2015.09.005

Kong, X., Moriya, J., Carle, V. et al. De novo development of proteolytically resistant therapeutic peptides for oral administration. Nat Biomed Eng 4, 560–571 (2020). https://doi.org/10.1038/s41551-020-0556-3