Erythropoietin as neuroprotective and neuroregenerative treatment strategy: Comprehensive overview of 12 years of preclinical and clinical research

Erythropoietin (EPO), originally discovered as hematopoietic growth factor, has direct effects on cells of the nervous system that make it a highly attractive candidate drug for neuroprotection/neuroregeneration. Hardly any other compound has led to so much preclinical work in the field of translational neuroscience than EPO. Almost all of the >180 preclinical studies performed by many independent research groups from all over the world in the last 12 years have yielded positive results on EPO as a neuroprotective drug. The fact that EPO was approved for the treatment of anemia >20 years ago and found to be well tolerated and safe, facilitated the first steps of translation from preclinical findings to the clinic. On the other hand, the same fact, naturally associated with loss of patent protection, hindered to develop EPO as a highly promising therapeutic strategy for application in human brain disease. Therefore, only few clinical neuroprotection studies have been concluded, all with essentially positive and stimulating results, but no further development towards the clinic has occurred thus far. This article reviews the preclinical and clinical work on EPO for the indications neuroprotection/neuroregeneration and cognition, and hopefully will stimulate new endeavours promoting development of EPO for the treatment of human brain diseases.

Introduction

Undoubtedly, there would be a tremendous need for effective neuroprotective and neuroregenerative treatment strategies. Most diseases of the nervous system are etiologically unclear, extremely heterogeneous, and non-curable, with chances being very low that within the next decades a cure will be available for any of them. Facing this disillusioning reality, and considering the enormous human and socio-economic burden to be expected with an increasingly aging society in industrialized countries, the urgent demand of neuroprotective/neuroregenerative treatment approaches becomes even more plausible. Neuroprotective treatments aim at an enduring improvement of symptoms and/or slowing of an ongoing disease process. Essentially all compounds that have been associated with a potential neuroprotective/neuroregenerative capacity target determinants of the final common pathway of many different diseases of the nervous system, e.g. apoptosis, oxidative stress, inflammation, metabolic dysfunction or compromised neuroplasticity.

Hardly any other compound has now over more than a decade attracted so much attention as candidate for neuroprotection/neuroregeneration than erythropoietin (EPO). Not many other drug candidates have triggered so many preclinical studies on entirely different disease models, investigated by multiple independent research groups worldwide, than EPO. This overwhelming amount of data on EPO, showing mostly positive results regarding neuroprotection and neuroregeneration, has also stimulated clinical research as reflected by a substantial number of ongoing clinical trials on EPO in nervous system indications (for review see¹). The few thus far published clinical studies all yielded positive results or at least positive signals to be further pursued.2, *3, 4, 5, 6

Astonishingly, despite this large number of positive data, no adequate continuous support for translation of these findings into the clinic has been provided. This stagnation of further development may be the result of a number of unfortunate coincidences: (1) The EPO industry strongly protects their lucrative anemia market that, for individual producers, has already been subject to shrinkage due to expired patents and popping-up of more and more biosimilar products. (2) Recent clinical trials in the anemia/oncology field have raised concerns regarding previously established indications. (3) In the absence of sufficient patent protection, new indications are not welcome since they bear the risk of as yet undetected additional side-effects of EPO that might further endanger the presently still highly profitable business. (4) Finally, there is an absurd reluctance of public funding agencies to support trials for new indications on compounds that are already approved and in their eyes should be supported by industry. This makes investigator-initiated trial designers going in time-, money-, and energy-consuming circles that ultimately lead nowhere. Therefore, even though EPO might be the most promising agent so far to provide neuroprotection/neuroregeneration in a broad field of neurological and psychiatric diseases, less effective and less well tolerated compounds are much more likely to be developed. Hopefully, the present review, summarizing the overall positive outcomes of preclinical as well as of clinical work, will stimulate novel attempts to conduct clinical trials on EPO treatment of brain diseases.

With this review, we provide a comprehensive but compacted overview of the more than 180 preclinical studies performed since 1998. In an especially designed master table (Table 1), the main results are briefly summarized. Five extensive supplementary tables encompass all available preclinical studies, with their main contents recapitulated shortly and commented on. In addition, we present in this article a brief synopsis of the few published clinical studies dealing with EPO treatment of neuropsychiatric diseases as well as an overview of work on healthy individuals, rodents and humans, set up to gain more mechanistic insight into the potent effects of EPO on cognitive performance. These positive effects on cognition have not sufficiently been explored yet for potential application in diseases characterized by cognitive decline. Ultimately, we will give an outlook regarding the most important next steps required to move the field towards clinical development.