运动中得基因治疗

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Gene therapy in sport
R J Trent and I E Alexander
[color=rgb(62,62,62)! important]R J Trent, Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital in the Central Clinical School, University of Sydney, NSW, Australia
[color=rgb(62,62,62)! important]I E Alexander, Gene Therapy Research Unit, The Children's Hospital, Westmead and Children's Medical Research Institute, Sydney, NSW, Australia
[color=rgb(62,62,62)! important]Correspondence to: Professor Trent
Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital in the Central Clinical School, University of Sydney, NSW 2050, Australia; rtrent@med.usyd.edu.au
[color=rgb(62,62,62)! important] This article has been cited by other articles in PMC.

Short abstract

The potential benefits of gene therapy for sports injuries are counterbalanced by the potential for gene doping
Keywords: gene therapy, injury, gene doping, cheating

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Human gene therapy involves the insertion of DNA (or RNA) into somatic cells to produce a therapeutic effect. Gene therapy was first envisaged as an approach to treating genetic disorders. In this scenario, missing or mutant genes could be replaced or repaired. Today, gene therapy has broader applications, with trials covering many clinical problems including genetic diseases, cancer, infections such as HIV, and degenerative diseases.
The transfer of genetic material into cells can be undertaken in many ways, most commonly using a viral vector. For this, viruses are genetically engineered to remove infectious potential while retaining the capacity to carry a therapeutic gene(s) into selected target cells. The inserted sequences can encode a missing or mutant product as might occur in the case of cancer, or alternatively could be used to inhibit a foreign protein as would be found in HIV infection. Viral vectors have been derived from a number of different viruses. Some, such as the adenovirus, are associated with relatively mild human infections, whereas others are associated with more serious disease, for example HIV. Certain viral properties are particularly useful for gene therapy, such as the capacity to permanently integrate introduced genetic sequences into the host cell genome.
Apart from viruses, there are numerous physicochemical methods for introducing DNA (or RNA) into somatic cells. The most relevant in the context of sport involves direct injection of DNA that has been formulated with a chemical carrier for more efficient uptake by cells. None of the physicochemical approaches has been successful in human trials, as the levels of gene transfer achieved are insufficient for therapeutic benefit.
The results in gene therapy have generally been disappointing despite over 1000 clinical trials since 1990.1 Only two diseases have been successfully treated by gene therapy. Both are forms of severe combined immunodeficiency, SCID‐X1 and ADA‐deficiency.2,3 Unfortunately, success has come at a cost, with three of 18 infants with SCID‐X1 treated developing leukaemia. This has now been shown to have been caused by insertional mutagenesis, which had previously been considered a remote theoretical risk associated with the integrating gene transfer technology used.
At present, there are three limitations to gene therapy: (a) gene transfer technologies are not efficient enough for most applications; (b) therapeutically useful integrating gene transfer technologies carry unresolved risks; (c) there remains an inadequate understanding of the biology of therapeutically relevant target cell populations.

Gene therapy and sporting injuries

There are a number of models illustrating how gene therapy may at some future time be used to treat sporting injuries (table 1​1).

Table 1 Human gene therapy studies with potential application to sport

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Gene doping in sport

Sports men and women and sporting administrators faced with the prospect of drug cheating and blood doping now need to consider gene doping.7 Although therapeutic benefit from gene therapy is difficult to achieve, gene doping is paradoxically more feasible because a very large output from the introduced gene may not be required, and the desired effect need only be short term. Regular injections at the time of sporting events may suffice. Gene doping is further simplified as it would not be necessary to have the transferred gene regulated so that its output corresponds to specific cellular requirements as might be the case for treating disease.
Genes of relevance to doping such as growth hormone, insulin‐like growth factor I, and erythropoietin have been cloned, and so are readily available. They could be used as an alternative way to produce a range of performance enhancing agents. The risks of taking these substances in the form of traditional chemicals are known, and so decisions about risk versus benefit are straightforward. The same cannot be said for gene doping, as there continue to be many unknowns in this form of cellular intervention. Effects cannot be predicted, and so the sportsperson taking this route for cheating does not have control of the product. Random integration of vector sequences, for example, could produce complications such as acute leukaemia or other forms of cancer. Finally, unlike taking a drug, gene transfer is not easy to reverse, and so any untoward effects may be long term. There is also a small risk of inadvertent gene transfer to germ cells with the potential for harm to be passed on to an athlete's children.
Today, the risks for gene doping are much greater than the taking of traditional chemical products. Those involved in sport should be sufficiently informed of the risks, as well as likely future benefits of gene therapy. As the technology improves, many of the complications may be avoided, and so ongoing assessment of the potential for gene doping will be necessary. Detecting gene doping cheats will be possible using the standard assays as well as through the identification of gene vectors or their products. The bypassing of various metabolic pathways through the insertion of genes may lead to changes in gene expression profiles, and this may open up another approach to detecting gene doping.

Footnotes

[color=rgb(62,62,62)! important]Competing interests: none declared

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References

1. Gene therapy clinical trials worldwide http://www.wiley.co.uk/genmed/clinical (accessed 19 Oct 2005)
2. Cavazzana‐Calvo M, Hacein‐Bey S, de Saint Basile G. et al Gene therapy of human severe combined immunodeficiency (SCID)‐X1 disease. Science 2000. 288669–672.672. [PubMed]
3. Aiuti A, Vai S, Mortellaro A. et al Immune reconstitution in ADA‐SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med 2002. 8423–425.425. [PubMed]
4. DelloRusso C, Scott J M, Hartigan‐O'Connor D. et al Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full‐length dystrophin. Proc Natl Acad Sci USA2002. 9912979–12984.12984. [PMC free article] [PubMed]
5. NASA Exploration Systems Mission Directorate Education Outreach http://weboflife.nasa.gov/curren ... ght/geneTherapy.htm (accessed 19 Oct 2005)
6. Evans C H, Robbins P D, Ghivizzani S C. et al Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci USA 2005. 1028698–8703.8703. [PMC free article][PubMed]
7. Haisma H J. Gene doping: a report from the Netherlands Centre for Doping Affairs. http://www.genedoping.com (accessed 19 Oct 2005)






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