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(Circulation Research. 2001;88:468.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Chimeric Smooth Muscle–Specific Enhancer/Promoters

Valuable Tools for Adenovirus-Mediated Cardiovascular Gene Therapy

Sébastien Ribault, Pascal Neuville, Agnès Méchine-Neuville, Fabrice Augé, Ara Parlakian, Giulio Gabbiani, Denise Paulin, Valérie Calenda

From the Cardiovascular Gene Therapy Laboratory (S.R., P.N., F.A., V.C.), Transgène S.A., Strasbourg, France; Department of Pathology (A.M.-N.), Hôpital de Hautepierre, Strasbourg, France; Molecular Biology of Differentiation Laboratory (A.P., D.P.), D. Diderot University, Paris, France; and Department of Pathology (G.G.), University of Geneva-CMU, Geneva, Switzerland.

Correspondence to Dr Valerie Calenda, Transgène S.A., Cardiovascular Gene Therapy Laboratory, 11 rue de Molsheim, 67082 Strasbourg, Cedex, France. E-mail calenda{at}transgene.fr

Abstract—Gene transfer with adenoviral vectors is an attractive approach for the treatment of atherosclerosis and restenosis. However, because expression of a therapeutic gene in nontarget tissues may have deleterious effects, artery-specific expression is desirable. Although expression vectors containing transcriptional regulatory elements of genes expressed solely in smooth muscle cells (SMCs) have proved efficient to restrict expression of the transgene, their use in the clinical setting can be limited by their reduced strength. In the present study, we show that low levels of transgene expression are obtained with the smooth muscle (SM)-specific SM22 promoter compared with the viral cytomegalovirus (CMV) enhancer/promoter. We have generated chimeric transcriptional cassettes containing either a SM (SM-myosin heavy chain) or a skeletal muscle (creatine kinase) enhancer combined with the SM22 promoter. With both constructs we observed significantly stronger expression that remains SM-specific. In vivo, reporter gene expression was restricted to arterial SMCs with no detectable signal at remote sites. Moreover, when interferon- expression was driven by one of these two chimeras, SMC growth was inhibited as efficiently as with the CMV promoter. Finally, we demonstrate that neointima formation in the rat carotid balloon injury model was reduced to the same extent by adenoviral gene transfer of interferon- driven either by the SM-myosin heavy chain enhancer/SM22 promoter or the CMV promoter. These results indicate that such vectors can be useful for the treatment of hyperproliferative vascular disorders.

Key Words: smooth muscle myosin • creatine kinase • interferon- • restenosis • gene transfer

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