Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene.

TLDR

Vascular disease is thought to arise from disturbances in the balance of factors controlling vascular tone and structure, and recent advances in in‑vivo gene transfer have demonstrated feasibility but no therapeutic studies using functional enzyme cDNA have yet been reported. The study tests whether endothelium‑derived nitric oxide acts as an endogenous inhibitor of vascular lesion formation. In a rat carotid balloon‑injury model, endothelial cell nitric oxide synthase was re‑expressed in the vessel wall using a highly efficient Sendai virus/liposome in‑vivo gene transfer technique. Transfection restored NO production and vascular reactivity, reduced neointima formation by 70 % at day 14, and provides direct evidence that NO inhibits smooth‑muscle proliferation and migration, supporting ec‑NOS gene therapy as a potential treatment for neointimal hyperplasia.

Abstract

It is postulated that vascular disease involves a disturbance in the homeostatic balance of factors regulating vascular tone and structure. Recent developments in gene transfer techniques have emerged as an exciting therapeutic option to treat vascular disease. Several studies have established the feasibility of direct in vivo gene transfer into the vasculature by using reporter genes such as beta-galactosidase or luciferase. To date no study has documented therapeutic effects with in vivo gene transfer of a cDNA encoding a functional enzyme. This study tests the hypothesis that endothelium-derived nitric oxide is an endogenous inhibitor of vascular lesion formation. After denudation by balloon injury of the endothelium of rat carotid arteries, we restored endothelial cell nitric oxide synthase (ec-NOS) expression in the vessel wall by using the highly efficient Sendai virus/liposome in vivo gene transfer technique. ec-NOS gene transfection not only restored NO production to levels seen in normal untreated vessels but also increased vascular reactivity of the injured vessels. Neointima formation at day 14 after balloon injury was inhibited by 70%. These findings provide direct evidence that NO is an endogenous inhibitor of vascular lesion formation in vivo (by inhibiting smooth muscle cell proliferation and migration) and suggest the possibility of ec-NOS transfection as a potential therapeutic approach to treat neointimal hyperplasia.