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The Skin as Detoxifier
By Lone Frank

Featured Article.

A team of Danish scientists has big plans for skin—they want to put it to use as a detoxifier. By employing gene therapy in skin cells, they propose to remove harmful compounds from the blood stream and are now gearing up to test the concept in a clinical trial. A long-term ambition is to treat people at risk for heart disease due to high cholesterol.

Nude Mouse (immunodeficient) with a transplanted patch of human skin grown in culture and genetically modified.

As the largest organ in our body, the skin has a significant capacity for producing and secreting proteins into circulation. Some research groups are working towards exploiting this for treating patients with growth hormone and supplying hemophiliacs with blood coagulation factors. A decade ago, the thought of turning this idea upside down began to surface. "We want to use the skin's ability to metabolize proteins and chemical compounds and employ it as a metabolic sink," says Thomas G. Jensen, of the Institute of Human Genetics at University of Århus. Its ample blood supply makes the skin metabolically highly active and able to take harmful metabolites out of the circulation. Putting it to work as a detoxifying unit could be relevant in several metabolic diseases.

The principle is to take skin cells or keratinocytes from patients, grow them in the lab and let a harmless retrovirus insert the genes necessary for the specific metabolic process into the cells' own genome. With a cocktail of growth factors, the modified keratinocytes are made to form a multilayered skin, which can be grafted onto the original donor without risk of rejection. "We know from treatment of burn victims that it blends in well with the normal skin," says Jensen. And while general enthusiasm for gene therapy has cooled following the recent death of a patient who suffered adverse reactions to the virus-transporting genes to his liver, skin still receives favorable reviews as a target. "In contrast to systemic delivery you can monitor all the modified cells and remove them if necessary," says Lorne Taichman, of Stony Brook's department of Oral Biology and Pathology, who is working with skin gene therapy.

Already, experiments with cell cultures show stable expression of high levels of enzyme

The Århus researchers currently collaborate with American colleagues on the first ever clinical trial using the metabolic sink concept. The team aims to employ genetically manipulated keratinocytes in treating patients with gyrate atrophy. Patients with this rare genetic disorder do not produce the enzyme ornithine amino transferase, and as a result they accumulate the metabolite ornithine in the blood. The high levels of ornithine cause degeneration of the retina and also lead to blindness. "The only known treatment is a very strict diet that most patients do not tolerate," observes Carl Csaky, of the National Eye Institute in Bethesda, Maryland. He proposes to use a small patch of genetically modified skin as "a furnace to burn the excess ornithine" and expects the go-ahead from authorities within six months. Researchers will then remove skin cells from the thigh area, modify them with the gene for ornithine amino transferase and transplant them back in the same place. Already, experiments with cell cultures show stable expression of high levels of enzyme, says Csaky. "The trial's first phase will monitor the production over time and make sure the cells are tolerated. The next step is to test how much skin is needed to get a therapeutic effect."

In Taichman's view, "The applicability of the metabolic sink concept for a given condition depends on whether a reasonably small patch of grafted skin can remove enough metabolites." Jensen hopes to make the method relevant to hypercholesterolemia—high levels of cholesterol in the blood—, which places millions of people at risk for heart disease. "In animal studies, atherosclerosis can be prevented by enhancing the expression of receptors that bind cholesterol," notes Jensen. With colleagues, he is now trying to engineer keratinocytes to express high levels of the Low-Density Lipoprotein (LDL) receptor. Embedded in the cell membrane, these receptors grab onto passing cholesterol particles and ferry them across to the inside. Cell culture experiments suggest that keratinocytes can be transfected with the LDL receptor gene, express high levels of the protein and then take up much more cholesterol than normal cells. "We have calculated that a patient would need a skin graft covering about half the upper arm," says Jensen. He hypothesizes that the sequestered cholesterol will leave the body when skin cells are naturally shed. This will now be tested in a mouse model, but while a treatment for patients may be years away, Taichman calls the idea "very elegant."

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Hengge, U.R., Taichman, L.B., Kaur, P., Rogers, G., Jensen, T.G., Goldsmith, L.A., Rees, J.L. & Christiano, A.M. How realistic is cutaneous gene therapy? Exp Dermatol 8, 419-431 (October 1999).
Sullivan, D.M., Jensen, T.G., Taichman, L.B. & Csaky, K.G. Ornithine-delta-aminotransferase expression and ornithine metabolism in cultured epidermal keratinocytes: Toward metabolic sink therapy for gyrate atrophy. Gene Ther 4, 1036-1044 (October 1997).

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