The World Anti-Doping Agency (WADA) has committed $50 million US dollars to research since 2001 (see their grant applications & projects here). Since 2007, some of those research funds have gone to the emerging problem of gene doping. Read about the first public evidence of gene doping, from the trial of the German track coach Thomas Springstein., in the NYT article Outlaw DNA.
So what is gene doping? WADA defines it as “the transfer of nucleic acids or nucleic acid sequences’ and/or ‘the use of normal or genetically modified cells with the intention to enhance sports performance.” Gene doping is based on a vector containing a therapeutic gene coupled with a regulatory element, delivered to somatic cells either in, or ex vivo. Plasmid based vectors have poor transfection efficiency and short duration of expression. Viral based vectors can cause deadly immune responses to the vector, but are difficult to detect by using anti-virus antibodies, given that they are based on commonly contagious, wild type viruses. Both gene doping methods can lead to autoimmune responses to the endogenous gene product made by the human body. Yikes, right?! There is no safe gene doping. The attraction lies in the idea that gene doping has been thought of as “undetectable”. However unlikely, gene doping is still an alternative to the sophisticated drug doping protocols, estimated to be used by up to 10% of high level athletes to stay just below detection thresholds.
Repoxygen™ is an example of technology at risk for gene doping, featured in the review by Elmo W.I Neuberger et al., Detection of EPO gene doping in blood. (2012) in Drug Testing and Analysis. Endogenous erythropoietin (EPO) circulates in our blood, stimulating the differentiation of red blood cell precursors cells in bone marrow. Thereby increasing our oxygen delivery. In Repoxygen™, a human EPO gene is delivered by intramuscular injection, within a viral vector with self regulated expression through a hypoxia response element. Many EPO-like or EPO stimulating drugs are available for treating anemia. Promising results in mice studies of Repoxygen™ were not enough for the developer, Oxford Biomedica to follow up with clinical trials in humans because of the presence of these alternative EPO drugs. Therapeutically these other drugs used by people with heriditary anemia, IDS, Cancer, etc require multiple injections. So technology like Repoxygen™ is still relevant. Several studies have used plasmic ‘mini circle’ vectors to improve safety of the technique in primates.
Currently, WADA prescribes the indirect Athlete Biological Passport (ABP) system to monitor athletes for responses due to doping over time. Indirect measures should catch any doping, no matter the method in theory. Again, this isn’t really ideal since cheaters can use doping protocols to beat this system. Some projects funded by WADA aim to develop detection methods specific to gene doping. A current focus of this research uses transcriptomics. Specifically, highly stable, circulating microRNA from serum, is being used to look for gene doping biomarkers. This approach will certainly require a large sample of the population and good bioinformatics to get it right. It may all work out. It’s conceivable that athletes will be seeking personalised genomics in the future to assess their performance abilities based on their gene expression. You can’t stop progress.
Neuberger EW, Jurkiewicz M, Moser DA, & Simon P (2012). Detection of EPO gene doping in blood. Drug testing and analysis PMID: 22508654