Gene prophylaxis by a DNA repair function

Gene therapy, the treatment of disorders or pathophysiologic states on the basis of the transfer of genetic information, has been thoroughly investigated for the treatment of lung illnesses, e.g. cystic fibrosis, alpha1-antitrypsin deficiency-related emphysema and cancer. Transfer of genetic information may be further used to elevate the level of protection of normal lung tissues in at risk individuals, with preventing purposes. This concept can be described by the term “gene prophylaxis”. Lying at the gas-exchange interface, lung epithelia may be at risk of oxidation-induced mutagenesis. Further, inflammation processes possibly consequent on smoking liberate reactive oxygen species (ROS) that multiply the carcinogenic effects of tobacco. Some studies report in lung cancer patients an high frequency of variations of the 8-oxoguanine DNA glycosylase (hOGG1) gene that encodes a sluggish glycosylase for oxidized purines. Unlike dietary interventions with antioxidant drugs that only allow temporary oxy-radical scavenging, reinforcing the DNA repair capacity in lung epithelia may afford long-term, steady protection from ROS-generated mutagenesis and carcinogenesis. In this regard, the Escherichia coli formamidopyrimidine DNA glycosylase (FPG) is a possible tool. FPG is 80-fold faster than hOGG1 in repairing oxidized purines and has broader substrate specificity. Cell culture studies have shown that FPG can be expressed in mammalian cells where it accelerates DNA repair and abates mutagenicity of a wide range of DNA damaging agents. Spontaneous mutagenesis drops too. Prophylaxis of oxidative DNA damage and mutation could be achieved in lung epithelia and other tissues of at-risk individuals by FPG expression. Currently available vehicles for this peculiar type of gene therapy are briefly surveyed.