Repoxygen

Repoxygen is the tradename for a type of gene therapy that induces controlled release of erythropoietin (EPO) in response to low oxygen concentration. It is has been developed by Oxford Biomedica to treat anaemia. It has been developed in mice, is still in preclinical development and has not been extensively tested in humans.

It is constructed as a viral gene delivery vector carrying the human EPO gene under the control of a so-called "hypoxia control element" (“HRE”). The HRE is claimed to sense low oxygen concentrations and to switch a gene on in response. Repoxygen is designed to be delivered by injection into muscle and therefore to induce syntheses of EPO in the muscle tissue. Normally, EPO is synthesized in the liver and kidneys. It leads to increased production of red blood cells.

Use of recombinate EPO DNA in mice has shown protective effects for epithelial cells and is being investigated as a prophylatic treatment for lung tissue injury.

Excess EPO, the signalling hormone for more red blood cell production (increased erythrocytes), can lead to erythrocytosis -- a condition of too many red blood cells. Erythrocytosis makes the blood thicker and more viscious, making pooling and clotting more likely, and represents an increased stress on the heart (due to the thicker blood). Erythrocytosis is potentially fatal, especially in endurance athletes who are frequently dehydrated during long events.

Doping

Athletes could consider using Repoxygen as a means of increasing their number of red blood cells. Due to its alleged self-regulating properties it may be impossible to detect Repoxygen currently. Repoxygen is prohibited both in and out of competition under the World Anti-Doping Code 2006 Prohibited List.

The German track and field coach Thomas Springstein and Rashid Ramzi are currently suspected to have used Repoxygen.

Repoxygen's delivery vector has triggered immune response in several cases and resulted in at least one confirmed death directly related to the body's immune response to the viral protein delivery vehicle.

The self-regulating properties of EPO are highly touted in cases of defficit, however such a property actually makes it less effective to suppliment natural EPO levels in athletes, so there may be fewer gains but this can in theory keep EPO levels under the acceptable range in testing. Gains from traditional EPO doping is detectable in blood samples for a few weeks after injection, eventually dissipating; Repoxygen's prolonged effect (permanent DNA insertion) would not let an athlete "test clean" without gene down-regulation (not currently possible by drug injection, though DNMT studies are making man-made control of genes just over the horizon). A doping athlete using repoxygen is either cheating and will test out of range for EPO, or they're "trying" to cheat and don't get any benefit beyond natural varience and acceptable EPO testing levels.

DNA sequencing for EPO genes is likely beyond any current sport organizations, however the EPO gene used in Repoxygen and other gene therapies is typically a truncated version with decreased potency compared to natural genes in humans. This custom-EPO gene would stand out in a sequencing of DNA, though locating the inserted gene may be difficult without manufacturer assistance regarding tissue-target of the vector and likely DNA insertion point of the gene. This essential testing information has been suggested for any gene therapy legally developed in the future, though is currently not required in many countries.

Sports without doping tests or regulation hold the most allure for this product. EPO is up-regulated in anoxic environments such as high-altitude climbing; Repoxygen and other gene therapies may find "legal doping" applications in such sports. High-altitude mountain climbing (i.e. attempting to summit Death Zone mountain peaks without supplemental oxygen), or extreme deep diving (requiring one to hold their breath for several minutes while diving 100+ feet) are but two examples.

The time dependant nature of EPO (once the blood goes apoxic, the gene is activated and EPO hormone is produced and secreted from the kidneys and liver, which through a cascade signalling system stimulates the production of erythrocytes), this therapy has little benefit for sprinters or events where VO2 Max levels are not being achieved regularly.

External links

* [http://www.oxfordbiomedica.co.uk/repoxygen.htm Oxford Biomedica Article]
* [http://www.dw-world.de/dw/article/0,2144,1344595,00.html German coach Tomas Springstein sacked by his club]
* [http://www.sciencenews.org/view/generic/id/35185/title/Finding_the_golden_genes Science news - Gene Doping]

Additional Reading

* Yoshimi M, Maeyama T, Yamada M, Hamada N, Fukumoto J, Kawaguchi T, Kuwano K, & Nakanishi Y. (2008). Recombinant human erythropoietin reduces epithelial cell apoptosis and attenuates bleomycin-induced pneumonitis in mice. "Respirology 13"(5). 639-645.
* Percy MJ. (2008). Familial erythrocytosis arising from a gain-of-function mutation in the HIF2A gene of the oxygen sensing pathway. "Ulster Medical Journal 77"(2). 86-88.