Perspectives de thérapie génique de la resténose

Abstract

Le traumatisme infligé à l’artère athéromateuse, que l’on dilate à l’aide d’un ballonnet, entraîne dans 30 % des cas une resténose dans les six mois suivant l’intervention. La réduction du calibre artériel est liée à l’hyperplasie intimale et au remodelage artériel. Le transfert dans les cellules musculaires lisses de la paroi artérielle de gènes codant pour des inhibiteurs de la prolifération cellulaire semble une voie thérapeutique prometteuse. Les produits des gènes thérapeutiques cytotoxiques (thymidine kinase du virus herpès associée à un traitement par le ganciclovir) ou cytostatiques (protéines Rb, Gax, eNOS) inhibent efficacement la prolifération des cellules musculaires lisses et l’hyperplasie de l’intima. De nombreux problèmes restent néanmoins à régler avant que la thérapie génique n’entre en pratique clinique : améliorer le vecteur (construction de vecteurs adénoviraux de deuxième et troisième générations, moins immunogènes) et l’efficacité du transfert génique dans les artères athéromateuses, mais aussi empêcher la dissémination du vecteur dans les autres organes.

Recurrent luminal diameter narrowing following balloon angioplasty of coronary arteries, referred to as restenosis, remains the main limitation of interventional cardiology. Restenosis is an important target for gene therapy since it is frequent (30% of patients), costly (estimated $2 billion annually), refractory to all pharmacological therapies, and related to smooth muscle cell proliferation which is an inviting target for molecular strategies based on our knowledge of gene-regulated cellular proliferation. Because cell division is ultimately controlled by intranuclear events, the protein product of genes selected for their antiproliferative effects usually remain inside the cells. Consequently, transfer of growth inhibitory genes needs to be efficient, i.e. to involve a large proportion of smooth muscle cells populating the angioplasty site. To date, adenoviral vectors are, by far, the most efficient vectors to perform in vivo arterial gene delivery in normal as well as atherosclerotic arteries. These vectors, as well as others, have been recently used to demonstrate that therapeutic genes encoding cytolytic (herpes virus thymidine kinase gene combined with ganciclovir treatment) or cytostatic (hypophosphorylatable Rb, Gax, eNOS...) products successfully inhibit smooth muscle cell proliferation and related intimal hyperplasia. Despite substantial progress, major technical issues remain to be addressed before gene therapy is applied to clinical restenosis. First generation recombinant adenoviruses evoke both cellular and humoral immune responses leading to local toxicity and transient gene expression. Moreover, low-efficiency of gene transfer to atherosclerotic arteries may further impair the biological effect of antiproliferative genes. Finally, local gene delivery in the vasculature poses the risk of vector dissemination as well as unexpected transgene expression in organs remote from the transfected site.