New perspectives in genetic therapies

Abstract

Advances in genomics over the last years have opened new perspectives in medicine. Applications to the diagnosis of inherited diseases and cancer as well have become a reality, while therapeutic applications emerge. This started with the safe production of therapeutic proteins by genetic engineering of cultured cells now followed by gene therapy. Introduction of therapeutic genes into diseased cells offers the potential to cure monogenic inherited diseases and also to better fight cancer. Thus it is in these two areas that the first proofs of efficacy have been obtained. Ex vivo retrovirus-mediated gene transfer into autologous hematopoietic stem cells has been shown to provide sustained correction of three forms of severe primary immunodeficiencies in about 120 patients up to now. This approach is now extended to the treatment of more prevalent conditions such as hemoglobinopathies. ln vivo gene transfer based on adeno associated viral vectors is being used with some success in the treatment of hemophilia B and of inherited retinopathies as well while being now tested with promise for inherited neuromuscular diseases. Injection of autologous, ex vivo modified T lymphocytes, engineered to express a chimeric antigen receptor (CAR) recognizing a membrane tumor-expressed antigen has been shown to control some forms of leukemia, a promising entry into the treatment of cancer by gene therapy. Genome editing based on engineered nucleases (such as the CRISPR/Cas 9 system) offers additional hopes for gene therapy either through gene inactivation or gene modification (correction). This new technology, however, still requires additional testing to assess its efficacy, notably in nondividing cells as well as its safety because of the potential risk for « off targets ». Some have advocated that this latter technology could be used in the future to fix deleterious mutations in early embryos or even improve health characteristics by gene modification! This approach appears, however, as medically useless in most cases while ethically highly questionable since it implies modification of the germ line genome.