Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 658–666 | Cite as

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

  • Michael Brines
  • Ann N. Dunne
  • Monique van Velzen
  • Paolo L. Proto
  • Claes-Goran Ostenson
  • Rita I. Kirk
  • Ioannis N. Petropoulos
  • Saad Javed
  • Rayaz A. Malik
  • Anthony Cerami
  • Albert Dahan
Research Article

Abstract

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 PainDetect 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.

Notes

Acknowledgments

This work was supported in part by a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant no. FES0908, the Swedish Research Council, ALF, and the Swedish Diabetes Association). The authors thank Ferdinand C Breedveld and Geertrui Betgen for invaluable assistance, as well as the subjects and their families for agreeing to participate in this trial.

References

  1. 1.
    Navarro JF, Mora C. (2005) Role of inflammation in diabetic complications. Nephrol. Dial. Transplant. 20:2601–4.CrossRefPubMedGoogle Scholar
  2. 2.
    Brines M, Cerami A. (2012) The receptor that tames the innate immune response. Mol. Med. 18:486–96.CrossRefGoogle Scholar
  3. 3.
    Brines M, et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. U. S. A. 101:14907–12.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Brines M, Cerami A. (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 264:405–32.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Woo M, Hawkins M. (2014) Beyond erythropoiesis: emerging metabolic roles of erythropoietin. Diabetes 63:2229–2231.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Corwin HL, et al. (2007) Efficacy and safety of epoetin alfa in critically ill patients. N. Engl. J. Med. 357:965–76.CrossRefGoogle Scholar
  7. 7.
    Robertson CS, et al. (2014) Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. Jama 312:36–47.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Brines M, et al. (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 105:10925–30.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Leist M, et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 305:239–242.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Collino M, et al. (2014) A non-erythropoietic peptide derivative of erythropoietin decreases susceptibility to diet-induced insulin resistance in mice. Br. J. Pharmacol. 171:5802–15.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    McVicar CM, et al. (2011) Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy. Diabetes. 60:2995–3005.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Schmidt RE, et al. (2011) Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. Exp. Neurol. 232:126–35.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ahmet I, et al. (2011) A small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage. Mol. Med. 17:194–200.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ahmet I, et al. (2013) Chronic administration of small nonerythropoietic peptide sequence of erythropoietin effectively ameliorates the progression of postmyocardial infarction-dilated cardiomyopathy. J. Pharmacol. Exp. Ther. 345:446–56.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bohr S, et al. (2013) Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns. Proc. Natl. Acad. Sci. U. S. A. 110:3513–8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Robertson CS, et al. (2013) Treatment of mild traumatic brain injury with an erythropoietinmimetic peptide. J. Neurotrauma. 30:765–74.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Robertson CS, et al. (2012) Neuroprotection with an erythropoietin mimetic peptide (pHBSP) in a model of mild traumatic brain injury complicated by hemorrhagic shock. J. Neurotrauma. 29:1156–66.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Patel NS, et al. (2011) A nonerythropoietic peptide that mimics the 3D structure of erythropoietin reduces organ injury/dysfunction and inflammation in experimental hemorrhagic shock. Mol. Med. 17:883–92.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dahan A, et al. (2013) ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol. Med. 19:334–45.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Heij L, et al. (2012) Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, doubleblind pilot study. Mol. Med. 18:1430–6.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Niesters M, et al. (2013) The erythropoietinanalogue ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Exp. Opin. Orphan Drugs 1:77–87.CrossRefGoogle Scholar
  22. 22.
    Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. (2012) Small-fibre neuropathies—advances in diagnosis, pathophysiology and management. Nat. Rev. Neurol. 8:369–79.CrossRefPubMedGoogle Scholar
  23. 23.
    Menichella DM, et al. (2014) CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy. Mol. Pain. 10:42.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ortmann KL, Chattopadhyay M. (2014) Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy. Brain Behav. Immun. 41:144–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Swartjes M, et al. (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and β-common receptor knockout mice. Anesthesiology. 115:1084–92.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Swartjes M, et al. (2013) Ketamine does not produce relief of neuropathic pain in mice lacking the β-common receptor (CD131). PLoS One. 8:e71326.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Swartjes M, et al. (2014) 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. Mol. Pain. 10:13.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Freynhagen R, Baron R, Gockel U, Tolle TR. (2006) painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr. Med. Res. Opin. 22:1911–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Bouhassira D, et al. (2004) Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 108:248–57.CrossRefPubMedGoogle Scholar
  30. 30.
    Hoitsma E, De Vries J, Drent M. (2011) The small fiber neuropathy screening list: Construction and cross-validation in sarcoidosis. Respir. Med. 105:95–100.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hays RD, Sherbourne CD, Mazel RM. (1993) The RAND 36-Item Health Survey 1.0. Health Econ. 2:217–27.CrossRefGoogle Scholar
  32. 32.
    Rolke R, et al. (2006) Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur. J. Pain. 10:77–88.CrossRefPubMedGoogle Scholar
  33. 33.
    Rolke R, et al. (2006) Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 123:231–43.CrossRefPubMedGoogle Scholar
  34. 34.
    (2002) ATS statement: guidelines for the six-minute walk test. Am. J. Respir. Crit. Care Med. 166:111–7.Google Scholar
  35. 35.
    Troosters T, Gosselink R, Decramer M. (1999) Six minute walking distance in healthy elderly subjects. Eur. Respir. J. 14:270–4.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Tavakoli M, Malik RA. (2011) Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. J. Vis. Exp. doi: 10.3791/2194.Google Scholar
  37. 37.
    Petropoulos IN, et al. (2014) Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest. Ophthalmol. Vis. Sci. 55:2071–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Muller C, et al. (2013) The nonhematopoietic erythropoietin analogue ARA 290 improves glucose tolerance by stimulating insulin secretion in spontaneously type 2 diabetic Goto-Kakizaki rats. Diabetologia. 56(Suppl 1):S268.Google Scholar
  39. 39.
    Dejager S, Schweizer A, Foley JE. (2012) Evidence to support the use of vildagliptin monotherapy in the treatment of type 2 diabetes mellitus. Vasc. Health Risk Manag. 8:339–48.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Baron R, Tolle TR, Gockel U, Brosz M, Freynhagen R. (2009) A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: Differences in demographic data and sensory symptoms. Pain. 146:34–40.CrossRefPubMedGoogle Scholar
  41. 41.
    Baron R, et al. (2013) Test and re-test of the painDETECT-Questionnaire. Presented at: Proceedings of the 4th International Congress on Neuropathic Pain; 2013 May 23–26; Toronto, Canada.Google Scholar
  42. 42.
    Tavakoli M, et al. (2011) Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet. Med. 28:1261–7.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tavakoli M, et al. (2013) Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 62:254–60.CrossRefPubMedGoogle Scholar
  44. 44.
    Drent M, Lower EE, De Vries J. (2012) Sarcoidosis-associated fatigue. Eur. Respir. J. 40:255–63.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Michael Brines
    • 1
  • Ann N. Dunne
    • 1
  • Monique van Velzen
    • 2
  • Paolo L. Proto
    • 2
  • Claes-Goran Ostenson
    • 3
  • Rita I. Kirk
    • 1
  • Ioannis N. Petropoulos
    • 4
    • 5
  • Saad Javed
    • 4
  • Rayaz A. Malik
    • 4
    • 5
  • Anthony Cerami
    • 1
  • Albert Dahan
    • 2
  1. 1.Araim PharmaceuticalsTarrytownUSA
  2. 2.Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
  4. 4.Centre for Diabetes and EndocrinologyInstitute of Human Development, Manchester Academic Health Science CentreManchesterUK
  5. 5.Weill Cornell Medical College in QatarQatar FoundationDohaQatar

Personalised recommendations