GENE DOPING - 101 A synopsis edited from: Tozaki T and Hamilton NA (2021). Control of gene doping in human and horse sports. Gene Ther 10.1038/s41434-021-00267-5
INTRODUCTION Gene doping is prohibited in human and equine competition alike. The World Anti-Doping Agency (WADA), Fédération Equestre Internationale (FEI) and International Federation of Horseracing Authorities (IFHA) are the internationally recognised industry bodies that oversee governance of the Olympics, equestrian events and horseracing internationally. These organisations have introduced regulations to prohibit gene doping. The WADA (https://www.wada-ama.org/) and IFHA (https://www.ifhaonline.org/) have also published definitions of gene doping (FIGURE 1) while the FEI (https:// inside.fei.org/) is yet to do so. In humans, gene editing is most likely to be performed on adults, and as such will not affect the germline. This contrasts with the situation in horses which could be gene edited as adults or prenatally, as zygotes or embryos. In fact, editing horses as early as possible in development is appealing to reduce mosaicism and increase the efficiency of the edit. The editing of racehorse embryos to create genetically modified animals would be a direct contravention of Stud Book and horseracing rules. With the recent publication of a method to gene edit horse embryos, this is a particular concern for Horseracing Authorities. Further, in human sports, the recipient of gene doping can consent to the doping treatment, while clearly horses cannot, adding a further dimension to the ethical problem of gene doping in animals.
WHAT IS GENE DOPING? WADA defines gene doping as the use of nucleic acids with the potential to enhance sport performance and can be broadly grouped into gene transfer, gene silencing and gene editing. Gene transfer involves the introduction of exogenous transgenes into living cells that normally is aimed at treating genetic disorders by facilitating expression of the transgene in the targeted cells. Erythropoietin gene therapy has been explored to treat renal failure, and insulin-like growth factor 1 to treat various causes of skeletal muscle loss. However, these two genes are very likely to be targeted for gene doping since the administration of their recombinant proteins is already prohibited by both equine and human anti-doping agencies.
Gene silencing technology suppresses translation by hybridising the mRNA with artificially synthesised antisense oligonucleotides. Gene doping by gene suppression or silencing would target genes with products that can negatively affect performance, such as myostatin (MSTN), which contains a variant in Thoroughbred racehorses that is associated with racing performance. Gene editing is a technique used to perform substitutions, insertions, deletions, inversions, or translocations. The three best known gene-editing systems are zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR being the fastest and cheapest to use leading to easy and reliable editing of targeted genes.
CONCLUSION Gene doping presents a progressing threat to the integrity of all forms of competitive sport. Although there is no evidence indicating that gene doping is being used currently in horses, the technology to apply many forms of gene doping already exists. Tests to detect inserted transgenes have been developed, but the detection of gene editing is still very difficult. While the most effective measure for anti-doping control is the introduction of doping tests, the broad range of possible targets means that a successful anti-gene doping programme will combine different types of detection testing, education, and surveillance, to send the message that gene doping will not be tolerated.
REGULATORY CONSIDERATIONS Gene doping regulations published online for the International Federation of Horseracing Authorities, IFHA International Agreement on Breeding, Racing and Wagering (IABRW) are continually updated and are summarised in TABLE 1. The most up to date versions are found at IFHA International Agreement.
FURTHER READING Tozaki T and Hamilton NA (2021). Control of gene doping in human and horse sports. Gene Ther 10.1038
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