A viral-based gene therapy strategy could one day lead to better protection for patients suffering from the skin cancer–predisposing genetic disorder xeroderma pigmentosum (XP).

Xeroderma pigmentosum is a skin disorder resulting from defects in one of seven different genes involved in DNA damage repair, designated XPA–XPG. Patients suffering from XP face a 1,000-fold increased risk of skin cancer, primarily because of an increased sensitivity to ultraviolet (UV)-induced DNA damage, and, although skin cancer can be relatively straightforward to treat surgically, the severity of the malignancies that can occur as a result of XP result in a typical lifespan of 30–40 years.

Xeroderma pigmentosum is a promising candidate for gene therapy–based treatment strategies, however, because the genes involved in this disease have been fairly well characterized, and the skin offers an easy target for vector delivery. In a new study, a team of investigators led by Carlos Menck of the Universidade de São Paulo (São Paulo, Brazil) describes their pilot effort to develop such a therapeutic agent (Proc. Natl. Acad. Sci. USA, online 14 December 2004, doi:10.1073/pnas.0406304101). Menck's team worked with a mouse strain containing an inactivated Xpa gene, mirroring the genetic defect seen in the largest percentage of human XP patients. This strain similarly exhibits a highly elevated risk of developing tumors in response to UV exposure. To counter the mutation, the researchers generated an adenoviral construct containing the cDNA for human XPA and then introduced the virus subcutaneously.

Strong XPA expression was detected in the skin surrounding the injection site, with particularly high expression in the area posterior to the injection. To test for protection against tumor formation, infected and mock-infected mice were subjected to a 4-day course of UV exposure. The mock-infected mice showed early abnormalities in response to irradiation; within 3 weeks of treatment, lesions were clearly visible on the skin surface, and by 2 months, the vast majority of the irradiated mice developed squamous cell carcinomas. By contrast, the infected mice closely resembled wild-type animals in their response to this treatment. A few weeks after the treatments ended, some mild lesions had appeared, but these soon disappeared, and none of the mice went on to manifest carcinomas, even after 5 months.

Menck and his colleagues indicate that this study should provide a strong incentive to develop such strategies further for the treatment of XP, and that pending resolution of some of the inherent hurdles involved in working with adenoviral vectors, this approach could offer a viable therapeutic solution for XP patients.