Gene Therapy for skin cancer - in Mice

The UT Southwestern Medical Center at Dallas must be in full press release mode, cause it's the second major (and interesting!) one they release in a week (AIDS spreading post-oral infection is the other one, which we covered earlier). This time its about gene therapy and skin cancer. Using a mouse model for xeroderma pigmentosum (a genetic disease causing extreme sensibility to sunlight and ultraviolet rays, which cause skin cancer), the researchers achieved the first successful gene therapy for skin cancer (caused by this particular deficiency, it isn't a cure for skin cancer you and me might get).

Usual digested and commented press release :

Researchers at UT Southwestern Medical Center at Dallas have successfully tested the first gene therapy for skin cancer, using a mouse model for the disease xeroderma pigmentosum, or XP. [...] XP is a debilitating disease in which patients must avoid the sun and all other sources of ultraviolet (UV) light. Exposure to UV light increases the risk for all cancers, but exposed skin is most prone to the disease. With a 10,000-fold increase in cancer risk, many XP sufferers eventually succumb to tumors at an early age.

To give you an idea of XP rarity as a disease, it occurs in 1 out of every 250,000 individuals within the United States and in 1 out of every 40,000 people in Japan. It pales when compared with more prevalent diseases, like diabetes, which affect 6.2 percent of the USA population. So why did they chose to work on this particular genetic defect? Let's see...

Mice with mutations in the gene Xpa suffer from XP and develop cancerous lesions on their skin within three weeks after UV light exposure. Dr. Errol Friedberg, professor and chair of pathology at UT Southwestern, in collaboration with Dr. Carlos F.M. Menck of the Institutes of Biomedical Sciences in Sao Paulo, Brazil injected the normal gene into mice suffering from XP. After treatment with the normal gene, the mice were free from disease. [...] When the body is exposed to UV light, the DNA in dividing cells can become damaged. Normally, the body enlists a group of proteins whose job it is to repair the sites of UV-induced damage. But in children with XP, mistakes in DNA caused by UV light cannot be fixed because of mutations in the genes for the repair proteins. DNA damage goes uncorrected, and as cells divide they accumulate numerous mutations. When these mutations occur in genes that normally suppress cancer, cells develop abnormally and cancer ensues. A mutation in any one of seven human genes involved in DNA repair is sufficient to cause XP. One of these genes is XPA. Humans with mutations in XPA are one the largest groups of XP patients. In their gene therapy study, Dr. Friedberg and colleagues injected the normal version of mouse Xpa into the mutant mice, using a disabled virus that infects multiple cells. They then exposed the mice to UV light for a few hours over several days. Five months after the last exposure - long after Xpa mutant mice would normally develop skin lesions - the treated mice merely had sunburn. The skin cells surrounding the site of the injection in the treated Xpa mutant mice were nearly identical to those of normal animals, indicating that the DNA repair mechanism had been restored by the addition of the normal Xpa gene, Dr. Friedberg said. Dr. Friedberg said he believes that with some technical refinement, this gene therapy technique may soon be applicable to all the mutations that cause XP in humans. "XP is a disease that lends itself well to gene therapy, for a variety of reasons," Dr. Friedberg said. "Most importantly, skin cells are highly accessible for introducing foreign genes. Also, infection of the skin with a virus carrying the gene of interest, as we did with the mice, allows for many, many cells to receive the appropriate gene. Once some of the existing technical limitations are solved these studies can hopefully be extended to trials with human XP patients."

So there you have it. We know the gene. Its easy to replace with a functional copy because the skin is highly accessible and permissive to this particular kind of therapy. Right now, viral-mediated gene transfer is riskier for vital organs such as the liver. Its a little sad that they didn't specify the virus vector they we're using; my guess would be an HIV-based retrovirus pseudotyped with VSV envelope for maximal efficiency, but I'll have to wait for the paper to be sure. I don't think this particular strategy is considered safe to use in humans yet, but we're getting there! Exciting time we're living in, isn't it?