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Gene therapy made difficult
  1. P A KINGSTON, Bristol-Myers Squibb Cardiovascular Research Fellow
  1. A M HEAGERTY, Professor of Medicine, University of Manchester
  1. Molecular Medicine Unit, Department of Medicine, University of Manchester
  2. Oxford Road, Manchester M13 9PT, UK
  3. email: MDMMSPAK@man.ac.uk

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Editor,—While we found your recent editorial on gene therapy very interesting,1 some points were raised that invite further comment.

Inflammatory responses seem inevitable following exposure to “first generation” adenovirus vectors; however, transgene selection appears to be an important factor in avoidance of these responses.

Your editorial states “ . . .(t)his inflammatory response is . . .generally observed using the sort of adenoviral loads needed to achieve expression of the transgene”. Undoubtedly, many early in vivo studies of adenovirus mediated gene therapy required very high virus doses to elicit significant transgene expression and therapeutic effects. However, a number of recent studies have obtained significant results with much lower virus doses. Sataet al, using an adenovirus expressing Fas-ligand (a cell surface/secreted protein), achieved a significant reduction in neointima formation with a dose of 1 × 106plaque forming units (pfu)—approximately 1000-fold lower than doses typically used in trials of cytostatic treatment.2 Shearset al demonstrated reduced neointima formation using an iNOS expressing vector at a similarly low virus dose (2 × 106 pfu).3 Therefore, in vascular tissues, transgenes giving rise to either a secreted protein or a protein that gives rise to a secreted product seem to afford some advantage, perhaps by requiring infection of only …

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