Abstract
Gene doping abuses the legitimate approach of gene therapy. While gene therapy aims to correct genetic disorders by introducing a foreign gene to replace an existing faulty one or by manipulating existing gene(s) to achieve a therapeutic benefit, gene doping employs the same concepts to bestow performance advantages on athletes over their competitors. Recent developments in genetic engineering have contributed significantly to the progress of gene therapy research and currently numerous clinical trials are underway. Some athletes and their staff are probably watching this progress closely. Any gene that plays a role in muscle development, oxygen delivery to tissues, neuromuscular coordination, or even pain control is considered a candidate for gene dopers. Unfortunately, detecting gene doping is technically very difficult because the transgenic proteins expressed by the introduced genes are similar to their endogenous counterparts. Researchers today are racing the clock because assuring the continued integrity of sports competition depends on their ability to develop effective detection strategies in preparation for the 2012 Olympics, which may mark the appearance of genetically modified athletes.
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Abbreviations
- ACE:
-
Angiotensin-converting enzyme
- cDNA:
-
Complementary DNA
- ELISA:
-
Enzyme-linked immunosorbent assay
- EPO:
-
Erythropoietin
- GH:
-
Growth hormone
- GHRH:
-
Growth hormone releasing hormone
- GTP:
-
Guanosine triphosphate
- HIFs:
-
Hypoxia-inducible factors
- IGF-1:
-
Insulin-like growth factor-1
- IL-6:
-
Interleukin-6
- INF-γ:
-
Interferon gamma
- ND:
-
Not detected
- PBMC:
-
Peripheral blood mononuclear cells
- PCR:
-
Polymerase chain reaction
- pDNA:
-
Plasmid DNA
- PEIs:
-
Polyethylenimines
- PEPCK-C:
-
Cytosolic phosphoenol pyruvate carboxykinase
- PLGA:
-
Poly(d,l-lactic-co-glycolic acid)
- PPAR-δ:
-
Peroxisome proliferator-activated receptor delta
- RBCs:
-
Red blood cells
- rAAV:
-
Recombinant adeno-associated virus
- rEPO:
-
Recombinant erythropoietin
- RG:
-
Resomer grade
- SB:
-
Sleeping beauty
- SELDI-TOF:
-
Surface enhanced laser desorption/ionization time-of-flight mass spectrometry
- siRNA:
-
Short interfering RNA
- TNF-α:
-
Tumor necrosis factor alpha
- VEGF:
-
Vascular endothelial growth factor
- WADA:
-
World Anti-Doping Agency
- X-SCID:
-
X-linked severe combined immunodeficiency
References
Amabile PG, Waugh JM, Lewis TN et al (2001) High-efficiency endovascular gene delivery via therapeutic ultrasound. J Am Coll Cardiol 37:1975–1980
Azzazy HM, Mansour MM (2007) Rogue athletes and recombinant DNA technology: challenges for doping control. Analyst 132:951–957
Azzazy HM, Mansour MM, Christenson RH (2005) Doping in the recombinant era: strategies and counterstrategies. Clin Biochem 38:959–965
Baoutina A, Alexander IE, Rasko JE et al (2007) Potential use of gene transfer in athletic performance enhancement. Mol Ther 15:1751–1766
Baoutina A, Alexander IE, Rasko JE et al (2008) Developing strategies for detection of gene doping. J Gene Med 10:3–20
Bidlingmaier M, Wu Z, Strasburger CJ (2003) Problems with GH doping in sports. J Endocrinol Invest 26:924–931
BRENDA: The Comprehensive Enzyme Information System. http://www.brenda-enzymes.org
Caldini A, Moneti G, Fanelli A et al (2003) Epoetin alpha, epoetin beta and darbepoetin alfa: two-dimensional gel electrophoresis isoforms characterization and mass spectrometry analysis. Proteomics 3:937–941
Cartier R, Reszka R (2002) Utilization of synthetic peptides containing nuclear localization signals for nonviral gene transfer systems. Gene Ther 9:157–167
Chaudhuri JD (2005) Genes arrayed out for you: the amazing world of microarrays. Med Sci Monit 11:RA52–RA62
Chenuaud P, Larcher T, Rabinowitz JE et al (2004) Autoimmune anemia in macaques following erythropoietin gene therapy. Blood 103:3303–3304
Chung L, Clifford D, Buckley M et al (2006) Novel biomarkers of human growth hormone action from serum proteomic profiling using protein chip mass spectrometry. J Clin Endocrinol Metab 91:671–677
Comerota AJ, Throm RC, Miller KA et al (2002) Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg 35:930–936
DeFrancesco L (2004) The faking of champions. Nat Biotechnol 22:1069–1071
Diamanti-Kandarakis E, Konstantinopoulos PA, Papailiou J et al (2005) Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era. Sports Med 35:831–840
Díez S, Tros de Ilarduya C (2006) Versatility of biodegradable poly(d, l-lactic-co-glycolic acid) microspheres for plasmid DNA delivery. Eur J Pharm Biopharm 63:188–197
Favre D, Provost N, Blouin V et al (2001) Immediate and long-term safety of recombinant adeno-associated virus injection into the nonhuman primate muscle. Mol Ther 4:559–566
Fink D, Mata M, Glorioso JC (2003) Cell and gene therapy in the treatment of pain. Adv Drug Deliv Rev 55:1055–1064
Furalyov VA, Kravchenko IV, Khotchenkov VP et al (2008) siRNAs targeting mouse myostatin. Biochemistry (Mosc) 73:342–345
Gaffney GR, Parisotto R (2007) Gene doping: a review of performance-enhancing genetics. Pediatr Clin N Am 54:807–822
Gao G, Lu Y, Calcedo R et al (2006) Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates. Mol Ther 13:77–87
Grimaldi PA (2005) Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment? Biochimie 87:5–8
Hackett PB, Ekker SC, Largaespada DA et al (2005) Sleeping beauty transposon-mediated gene therapy for prolonged expression. Adv Genet 54:189–232
Haisma HJ, de Hon O (2006) Gene doping. Int J Sports Med 27:257–266
Hakimi P, Yang J, Casadesus G et al (2007) Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem 282:32844–32855
Hautala AJ, Leon AS, Skinner JS et al (2007) Peroxisome proliferator-activated receptor-delta polymorphisms are associated with physical performance and plasma lipids: the HERITAGE family study. Am J Physiol Heart Circ Physiol 292:H2498–H2505
Hernandez YJ, Wang J, Kearns WG et al (1999) Latent adeno-associated virus infection elicits humoral but not cell-mediated immune responses in a nonhuman primate model. J Virol 73:8549–8558
Hruskovicová H, Dzurenková D, Selingerová M et al (2006) The angiotensin converting enzyme I/D polymorphism in long distance runners. J Sports Med Phys Fitness 46:509–513
Inazawa T, Tanabe T, Yamada H et al (2001) Glucocorticoid-regulated expression of exogenous human growth hormone gene in rats. Mol Ther 4:267–272
Issaq HJ, Veenstra TD, Conrads TP et al (2002) The SELDI-TOF MS approach to proteomics: protein profiling and biomarker identification. Biochem Biophys Res Commun 292:587–592
Jager L, Ehrhardt A (2007) Emerging adenoviral vectors for stable correction of genetic disorders. Curr Gene Ther 7:272–283
Joos L, Eryuksel E, Brutsche MH (2003) Functional genomics and gene microarrays – the use in research and clinical medicine. Swiss Med Wkly 133:31–38
Judge AD, Sood V, Shaw JR et al (2005) Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 23:457–462
Kaiser I (2003) Seeking the cause of induced leukemia in X-SCID. Science 24:495
Khan AS, Brown PA, Draghia-Akli R (2005) Plasmid-based growth hormone-releasing hormone supplementation and its applications. Curr Opin Mol Ther 7:306–316
Koshkina NV, Agoulnik IY, Melton SL et al (2003) Biodistribution and pharmacokinetics of aerosol and intravenously administered DNA-polyethyleneimine complexes: optimization of pulmonary delivery and retention. Mol Ther 8:249–254
Lasne F, Martin L, de Ceaurriz J et al (2004) “Genetic doping” with erythropoietin cDNA in primate muscle is detectable. Mol Ther 10:409–410
Lee S, Barton ER, Sweeney HL et al (2004) Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats. J Appl Physiol 96:1097–1104
Lemkine GF, Demeneix BA (2001) Polyethylenimines for in vivo gene delivery. Curr Opin Mol Ther 3:178–182
Lippi G, Guidi GC (2004) Gene manipulation and improvement of athletic performances: new strategies in blood doping. Br J Sports Med 38:641
Lippi G, Franchini M, Salvagno GL et al (2006) Biochemistry, physiology, and complications of blood doping: facts and speculation. Crit Rev Clin Lab Sci 43:349–391
Liu D, Ren T, Gao X (2003) Cationic transfection lipids. Curr Med Chem 10:1307–1315
Macarthur DG, North KN (2005) Genes and human elite athletic performance. Hum Genet 116:331–339
Manno CS, Chew AJ, Hutchison S et al (2003) AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101:2963–2972
Manno CS, Pierce GF, Arruda VR et al (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12:342–347
McCrory P (2003) Super athletes or gene cheats? Br J Sports Med 37:192–193
Medarova Z, Pham W, Farrar C et al (2007) In vivo imaging of siRNA delivery and silencing in tumors. Nat Med 13:372–377
Morrissey DV, Lockridge JA, Shaw L et al (2005) Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 23:1002–1007
Nathwani AC, Davidoff AM, Hanawa H et al (2002) Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques. Blood 100:1662–1669
Niidome T, Huang L (2002) Gene therapy progress and prospects: nonviral vectors. Gene Ther 9:1647–1652
Oh YK, Kim JP, Hwang TS et al (2001) Nasal absorption and biodistribution of plasmid DNA: an alternative route of DNA vaccine delivery. Vaccine 19:4519–4525
Parker SE, Borellini F, Wenk ML et al (1999) Plasmid DNA malaria vaccine: tissue distribution and safety studies in mice and rabbits. Hum Gene Ther 10:741–758
Pascual JA, Belalcazar V, de Bolos C et al (2004) Recombinant erythropoietin and analogues: a challenge for doping control. Ther Drug Monit 26:175–179
Quezada A, Larson J, French M et al (2004) Biodistribution and safety studies of hDel-1 plasmid-based gene therapy in mouse and rabbit models. J Pharm Pharmacol 56:177–185
Reilly SM, Lee CH (2008) PPAR delta as a therapeutic target in metabolic disease. FEBS Lett 582:26–31
Rip J, Nierman MC, Sierts JA et al (2005) Gene therapy for lipoprotein lipase deficiency: working toward clinical application. Hum Gene Ther 16:1276–1286
Rittner K, Benavente A, Bompard-Sorlet A et al (2002) New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. Mol Ther 5:104–114
Romero NB, Braun S, Benveniste O et al (2004) Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther 15:1065–1076
Schertzer JD, Lynch GS (2006) Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury. Gene Ther 13:1657–1664
Schuelke M, Wagner KR, Stolz LE et al (2004) Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350:2682–2688
Sebestyen MG, Hegge JO, Noble MA et al (2007) Progress toward a nonviral gene therapy protocol for the treatment of anemia. Hum Gene Ther 18:269–285
Shyu KG, Chang H, Wang BW et al (2003) Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia. Am J Med 114:85–92
Siess DC, Vedder CT, Merkens LS et al (2000) A human gene coding for a membrane-associated nucleic acid-binding protein. J Biol Chem 275:33655–33662
Somia N, Verma IM (2000) Gene therapy: trials and tribulations. Nat Rev Genet 1:91–99
Suda T, Gao X, Stolz DB et al (2007) Structural impact of hydrodynamic injection on mouse liver. Gene Ther 14:129–137
Sweeney HL (2004) Gene doping. Sci Am 291:62–69
Tentori L, Graziani G (2007) Doping with growth hormone/IGF-1, anabolic steroids or erythropoietin: is there a cancer risk? Pharmacol Res 55:359–369
Thomas SM, Zeng Q, Dyer KF et al (2003) Tissue distribution of liposome-mediated epidermal growth factor receptor antisense gene therapy. Cancer Gene Ther 10:518–528
Tiong A, Freedman SB (2004) Gene therapy for cardiovascular disease: the potential of VEGF. Curr Opin Mol Ther 6:151–159
Unal M, Ozer Unal D (2004) Gene doping in sports. Sports 34:357–362
Voutetakis A, Bossis I, Kok MR et al (2005) Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders. J Endocrinol 185:363–372
WADA (World Anti-Doping Agency); http://www.wada-ama.org , cited 25 Jan 2009
Wang YX, Zhang CL, Yu RT et al (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2:e294
Whittemore LA, Song K, Li X et al (2003) Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 300:965–971
Widera G, Austin M, Rabussay D et al (2000) Increased DNA vaccine delivery and immunogenicity by electroporation in vivo. J Immunol 164:4635–4640
Wilber RL (2002) Detection of DNA-recombinant human epoetin-alpha as a pharmacological ergogenic aid. Sports Med 32:125–142
Wolff JA, Budker V (2005) The mechanism of naked DNA uptake and expression. Adv Genet 54:3–20
Yew NS, Zhao H, Wu IH et al (2000) Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs. Mol Ther 1:255–262
Yoshida S, Kashiwamura SI, Hosoya Y et al (2000) Direct immunization of malaria DNA vaccine into the liver by gene gun protects against lethal challenge of Plasmodium berghei sporozoite. Biochem Biophys Res Commun 271:107–115
Zhang JS, Liu F, Conwell CC et al (2006) Mechanistic studies of sequential injection of cationic liposome and plasmid DNA. Mol Ther 13:429–437
Zhou S, Murphy JE, Escobedo JA et al (1998) Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates. Gene Ther 5:665–670
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Azzazy, H.M.E. (2010). Gene Doping. In: Thieme, D., Hemmersbach, P. (eds) Doping in Sports: Biochemical Principles, Effects and Analysis. Handbook of Experimental Pharmacology, vol 195. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-79088-4_20
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