Erythropoietin gene doping: facts and fictions

The substances and methods forbidden to increase the mass of hemoglobin (Hb) in sports (“blood doping”) include red blood cell (RBC) transfusion, Hb infusion, recombinant or chemical agents that stimulate the erythropoietin receptor, erythropoietin gene (EPO) transfer, and misuse of drugs activating endogenous EPO expression. The two latter possibilities are considered in this article. EPO transgenes have been explored in animal studies and in seminal human trials. However, the method is still not well engineered, despite almost 10 years of clinical studies. The menacing detriment of EPO transfer is immunogenicity of the transgenic DNA or cells and of the secreted recombinant proteins, respectively. However, since chemicals are available that activate EPO-controlling transcription factors, these compounds may also be misused in sports. The chemicals include inhibitors of GATA, which prevent GATA-2 from suppressing the EPO promoter, and stabilizers of the hypoxia-inducible transcription factors (HIFs), which activate the EPO enhancer. While there is a hope that EPO transfer has not yet entered the sports scene as a means of blood doping, drugs that increase endogenous EPO expression must be considered as a realistic threat with regard to doping efforts. In particular, there is suspicion that cobaltous salt, which is a potent stimulator of EPO when taken orally, could be misused by athletes.