Cytostatic gene therapy for occlusive vascular disease

Abstract

The formation of occlusive vascular lesions during the course of atherosclerosis, in-stent restenosis, transplant vasculopathy and vessel graft failure is a chronic inflammatory process characterised by excessive cellular proliferation within the injured artery wall. Therefore, candidate targets for the treatment of vasculoproliferative disease include cell cycle regulatory factors, such as cyclin-dependent kinases (CDKs), cyclins, CDK inhibitory proteins (CKIs), tumour suppressors, growth factors and their receptors, and transcription factors involved in cell cycle control. Although several genetically-modified mouse models have conclusively demonstrated that increased cell proliferation aggravates atheroma development, the potential benefit of cytostatic strategies for the treatment of atherosclerosis in the clinic is doubtful because human atherosclerosis is often diagnosed at advanced stages when neointimal proliferation appears low or absent. In contrast, restenosis and graft atherosclerosis appear amenable for cytostatic strategies because neointimal lesions typically develop over a short period of time after revascularisation (e.g., 2 – 12 months) and are localised at the site of the intervention. Vascular interventions, both endovascular and open surgical, allow minimally invasive, easily monitored gene delivery. In this review, the preclinical studies and clinical trials utilising cytostatic gene therapy for occlusive vascular disease will be discussed.

Keywords::

• atherosclerosis
• bypass graft failure
• cell cycle
• gene therapy
• restenosis

Acknowledgements

We apologise to many colleagues whose primary work has not been directly cited due to space constraints. We thank MJ Andrés-Manzano for the preparation of figures. Work in the laboratory of VA is supported by grants from Instituto de Salud Carlos III (Red de Centros RECAVA, C03/01), from Generalitat Valenciana (GV04B-288), from the Spanish Ministry of Education and Science and the European Regional Development Fund (SAF2004-03057), and from Laboratorios INDAS SA.