Reduction of hypertrophic scar via retroviral delivery of a dominant negative TGF-beta receptor II.

Abstract

Effective blockade of the pluripotent cytokine transforming growth factor (TGF)-beta as a means of cutaneous scar reduction is a strategy with great potential. This desired effect may be achieved through the overexpression of mutant TGF-beta receptors within the wound milieu. Our goal was to examine the effects of dominant negative mutant TGF-beta receptor II (TGFbetaRIIdn) protein expression in a well-established rabbit ear model of hypertrophic scarring. Serial injections of a retroviral construct encoding a truncated TGFbetaRII and the marker green fusion protein (pMSCV-rIIdn-GFP) were performed in 7mm punch wounds at day 10 and day 12 (two-day injection group) or days 8, 10, 12 (three-day injection group) post-wounding. Delivery of an empty vector (pMSCV-GFP) at the same time points served as a negative control. Histomorphometric analysis of wounds harvested at day 28 revealed a modest, though statistically significant reduction (20%, p=0.027) in the scar elevation index (SEI) in two-day treated and a more modest reduction in SEI (12%) in the three-day treated arm compared to null-treated controls. Confocal microscopy confirmed stable, yet variable transfection of the construct in both peri-wound tissue as well as rabbit dermal fibroblasts transfected in vitro. Optimisation of this novel application in retroviral gene therapy could lead to effective anti-scarring strategies.