Gene Doping

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Gene Doping

• Bruce Lynn
• Drugs, Ethics and Medico-legal Issues in Sport
• SURG G004

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• Plan of lecture
• How much do we know about performance related
  genes. Examples ACTN3, ACE.
• Where are we with gene modification technology?
  Look at what is happening in gene therapy. Mouse
  experiments with IGF2 gene to produce muscle
  hypertrophy.
• Discuss some of the key issues for sport

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92 gene entries and QTL associated
with performance or fitness phenotypes
PERUSSE, 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.12481264,
2003.
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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
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?-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.
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Other examples ACE insertion deletion
polymorphism Adrenaline receptor beta
2 AMP-activated protein kinase (AMPK) Iincreased
muscle glycogen
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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. 73627631, 2003
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• Methods for gene manipulation
• Harvest cells, manipulate ex-vivo, then
  re-introduce. E.g. Method used for treating the
  SCID children.
• 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.

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From Kresina and Branch, Chapt 1, in An
introduction to molecular medicine and gene
therapy, ed T.F.Kresina, 2001, Wiley
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From Kresina and Branch, Chapt 1, in An
introduction to molecular medicine and gene
therapy, ed T.F.Kresina, 2001, Wiley
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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, 1560315607, 1998
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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, 1560315607, 1998
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• Discussion the key issues for sport
• 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?
• Can gene doping be detected, i.e. can the
  authorities police its use anyway?
• What happens when parents select/manipulate
  embryos to create champions are we going to ban
  the children?