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Gene Doping Bruce Lynn Drugs, Ethics and Medico-legal Issues in Sport SURG G004 Plan of lecture: 1. How much do we know about performance related genes. Examples ACTN3, ACE. 2. Where are we with gene modification technology? Look at what is happening in gene therapy. Mouse experiments with IGF2 gene to produce muscle hypertrophy. 3. Discuss some of the key issues for sport: 92 gene entries and QTL associated with performance or fitness phenotypes PE´RUSSE, L., T. RANKINEN, R. RAURAMAA, M. A. RIVERA, B. WOLFARTH, and CLAUDE BOUCHARD. The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2002 Update. Med. Sci. Sports Exerc., Vol. 35, No. 8, pp.1248–1264, 2003. 2005 update has: 165 genes/QTL on autosomal chromosomes 5 on the X chromosome 17 mitochondrial genes Rankinen, T. et al (2006) Med Sci sports Ex 38 (11) 1863 -actinen 3 Actin binding protein. Found in Z-line of type 2, fast twitch, fibres. -actinen 2 is closely related and appears to have similar function. Nevertheless 2 separate genes have been conserved, ACTN2 and ACTN3. ACTN2 is on chromosome 1p42-43 ACTN3 is on chromosome 11p13-14 A polymorphism on ACTN3, 577X, introduces a stop codon and means 577XX individuals homozygous for this variant have no -actinen 3. They do have -actinen 2 and until last year no-one thought the absence of -actinen 3 made any difference. Other examples: ACE insertion deletion polymorphism Adrenaline receptor beta 2 AMP-activated protein kinase (AMPK) Iincreased muscle glycogen ACTN3 gene, R577X polymorphism. 577XX homozygotes have no - actinen 3 in the Z-line. Elite endurance athletes are significantly more likely to be 577XX, whilst elite power athletes are never 577XX, i.e. always have -actinen 3 present. Yang et al, Am. J. Hum. Genet. 73:627–631, 2003 Methods for gene manipulation 1. Harvest cells, manipulate ex-vivo, then re-introduce. E.g. Method used for treating the SCID children. 2. Directly inject the viral vector into the body, either systemically or into chosen tissue. E.g. Method used in trials of VEGF gene injection to poorly vascularised heart muscle in patients with heart disease. See next 2 slides. From Kresina and Branch, Chapt 1, in An introduction to molecular medicine and gene therapy, ed T.F.Kresina, 2001, Wiley From Kresina and Branch, Chapt 1, in An introduction to molecular medicine and gene therapy, ed T.F.Kresina, 2001, Wiley Injection of a recombinant adeno-associated virus directing overexpression of insulin-like growth factor I (IGF-I). Into the the anterior muscle compartment of mice. Examined 4-9 months later, Ext Digi Longus shown. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function E. R. BARTON-DAVIS et al, Proc. Natl. Acad. Sci., 95, 15603–15607, 1998 Cross sectional area (CSA) and tetanic force. Injected/contralateral uninjected EDL muscle. Mice 4-9 months after one injection of AAV construct for IGF-1 E. R. BARTON-DAVIS et al, Proc. Natl. Acad. Sci., 95, 15603–15607, 1998 Discussion: the key issues for sport: 1. If gene therapy is used for curing disease, will it then be used for fixing marginal insufficiencies and for aiding recovery from injury? If so will there be a clear enough line between these uses and performance enhancement? 2. Can gene doping be detected, i.e. can the authorities police its use anyway? 3. What happens when parents select/manipulate embryos to create champions – are we going to ban the children?
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