GENE THERAPY IN SPORTS

1. GENE THERAPY IN SPORTS Mechanisms & Bioethics

2. Gene Therapy • Gene transfer in somatic cells to heal or treat disorders • Strategy that can be applied to: chronic,acute or preventive treatments hereditary or acquired diseases

3. Why “somatic” • Somatic cells do not contribute to the germ line • Germ cells alterations will be transmitted to progeny

4. Gene transfer manner • Ex vivo: cells explanted-cultured-gene transfer-transformed-reinfused • In vivo local: intramuscular, intrajoint etc, localised diseases indication,limits toxicity of gene transfer & contamination of germ line • In vivo systemic:intravascular,intraperitoneal- no specific trapping, germ line ?

5. Non Viral & Viral transfer vehicles • Non viral: cell membrane not strong barrier but lack of transport into cell nucleous • Viral: get internalised,remain protected from cytoplasmic enzymes,genetic load into nucleous

6. Non viral • Naked DNA: complex formulations into liposomal particles • Oligonucleotides: small gene fragments, swamp pathological factors,gene repair inducers, short persistance (good candidates in transient treatments in doping arena)

7. Viral • Adenoviruses: favourite system,relatively large,can carry big gene, valnerable to attack from immune system • Adeno-associated viruses(AAVs):smaller, less valnerable,transfer small-size genes • Retroviruses: risk of insertional mutagenesis, can affect non dividing cells (ex: brain)

9. Gene therapies that can be abused in sports • Systemic proteins:EPO,growth hormone • Wound or injury healing: bone repair factors,PDGF, KGF • Increase muscle mass: angiogenic factors to skeletal and heart muscle,IGF 1 • Blood vessel growth:FGF-1,2,4 or 5, vascular endothelial growth factor

10. …. • Pain relief: endorphins, enkefalins, analgesic peptides • Neurological: hormone/growth factors, pituitary/hypothalamic cognition/memory enhancers,mood altering

11. Feared potential side effects • Viral vectors can stimulate immune system (acute toxic shock) • Repeated dosing leads to antibodies against virus which is stopped before gene delivery (ex. Muscle damage through exercise) • Over expression (monkeys with too much EPO need bleeding)- new nucleotides insertion to switch on/off the gene(Lin et al)

12. Side effects • Expressed gene product can be recognised as non self in individuals(factor VII in haemophiliac dogs) • Random integration in the genome (oligonucleotides) is genotoxic- increases risk of cancer • Germ cell contamination

13. Ways to detect Gene therapy • Antibodies to viral proteins- viral DNA • Quantitative gene chip analysis before and after • Over/under expressed gene’s product New Scientist journal, “gene cheats” 2000

14. Ethics • Accumulation of values and principles that address questions of what is good or bad in human affairs www.austlii.edu.au/au/other/alrc protection of human genetic information

15. Bioethics • The Romantic View integrity of sport threatened by technology • The Entertainment View extraordinary performance- genetic modification desirable • The Techno-Centered View GM simply a sophisticated technological character –eventualy can make the game fair

16. Is “natural” mutation an unfair advantage? • Eero Mantyranta two golden medals in cross-county skiing in 1964 Winter Olympics • Mutation in gene that produces the receptor for EPO • O2 normal- EPO receptor should shut down epo production but not in Mantyranta (mutation turned off this crucial feedback)

17. questions • “Elite” genes • Pre selection of athletes according to geno type • Bioethics about children and even embryos • DNA data of the whole population with severe even political implications