Abstract
To provide additional context, it is important to understand the following brief history of doping in athletic competition. Originally, athletes had special access to an improved diet and natural substances that were perceived to enhance performance. Throughout history this was acceptable practice to achieve an advantage. The widespread use of coca leaf was evident in the late nineteenth century, and European cyclists began to use mixtures of wine and cocaine. Coaches developed unique formulations of cocaine and caffeine until the substances became regulated in the 1920s. After this period, steroid use was believed to be common in the German army, and use of amphetamines by soldiers was encouraged during World War II. As pharmaceuticals became more sophisticated in the alteration of specific pathways there was increasing use of illegal small-molecule drugs among elite athletes. Worldwide recognition of the problem of doping in athletic competition was evident after the unification of Germany, with the admission that East German swimmers had been acknowledged abusers of anabolic steroids for 20 years, starting in the 1960s. It was during this era that a foundation was established by the International Olympic Committee to test athletes for a limited list of substances. France was the first to adopt antidoping legislation in 1963, following a number of tragic deaths among elite cyclists. During the Reagan administration in the United States, the 1988 Anti-Drug Abuse Act was passed and mandatory testing was implemented in many sports, but not until 1999 was the World Anti-Doping Agency (WADA) formed. At present, the WADA is the main clearinghouse for evaluation of doping in sport, and the prohibited substances list that is maintained by the WADA now clearly lists the newest category for abuse through “transfer of nucleic acids or nucleic acid sequences and the use of normal or genetically modified cells.” Friedmann and colleagues (2010) have recognized that advances in gene therapy have “set the stage for the next generation of illegal doping and doping detection in sport.” In 2004, the first report of AAV-mediated expression of IGF-I was considered for its potential to enhance muscle performance (Sweeney, 2004), and over the past 8 years a series of studies has raised key questions about abuse of otherwise therapeutic genes (Harridge and Velloso, 2009) or methods of detection (Ni et al., 2011).
In the current issue of Human Gene Therapy, Macedo and colleagues (2012) identify several important new findings and concepts related to gene transfer for enhancement of skeletal muscle performance via the IGF-I pathway. First, the effect of IGF-I overexpression led to effects in mice that mimicked endurance exercise. There was evidence of hypertrophy, neovascularization, and transition of fast to slow fibers. Therefore, the mice exhibited a significant gain in endurance as measured by bouts of intense swimming. The detailed analysis of downstream effects in muscle also provides some insight into how gene doping may be detected. For example, they quantified changes in protein expression by two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry. These measures were well correlated with changes in functional outcome. This approach looks at the proteomic changes associated with IGF-I doping and opens the door to a novel set of assays that would be designed to detect the downstream products of gene doping in plasma. Several unique signature proteins as well as mitochondrial function are altered in the presence of IGF-I overexpression. The ability to detect doping in this model is encouraging because blood- and urine-based assays are currently the established practice of the WADA. The strategy of IGF-I augmentation may be of value in the therapy of a variety of muscle weakness syndromes, so proper monitoring would help ensure proper use of this technology in the future.
Needless to say, there are significant risks associated with somatic cell modification for transient improvements in muscle performance, and therefore monitoring will be key to avoid abuse of this technology. Current efforts in muscle-directed gene transfer with AAV vectors are proceeding carefully, with an emphasis on safety. Therapeutic gene transfer in muscle is at an early stage and evidence of clinical success as well as safety has been observed in a number of severe inherited muscle diseases (Mendell et al., 2010a,b; Byrne et al., 2011). Safety trumps winning, and therefore it is important for the gene therapy community to remain vigilant that well-intentioned therapeutic strategies are not diverted toward enhancement of athletic performance.