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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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