title: Functional lentiviral vectors for xeroderma pigmentosum gene therapy.
abstract: Xeroderma pigmentosum (XP) is a genetic disease characterized by an autosomal-transmitted genodermatosis involving impaired DNA repair activity, where XP patients present severe sensitivity to sunlight (UVB radiation) and are highly victimized by skin cancer. Complementing XP genes by gene therapy is one potential strategy for helping XP patients. However, current viral-based protocols still lack long-term and stable expression, due to limited post-mitotic infection and gene silencing (in the case of retroviruses) or transient expression and activation of immune response (in the case of adenoviruses). Here we demonstrate that the use of third-generation lentiviral vectors can overcome some of these limitations, rescuing the aberrant phenotype in different categories of the disease (XPA, XPC and XPD). Our results show that lentiviruses are efficient tools to transduce XP fibroblasts and correct repair-defective cellular phenotypes by recovering proper gene expression, normal UV survival and unscheduled DNA synthesis after UV radiation. We propose lentiviral vectors as an attractive alternative for gene therapy protocols focusing on DNA repair genetic diseases.
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA, USA.
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Carlos F M
authors.initials: CF
authors.lastname: Menck
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
mesh_terms: D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000473:pathology / Q000628:therapy