Gene therapy of radiation fibrosis using adenovirus expressing decoy wnt receptor (sLRP6E1E2)

Abstract

Progressive fibrosis of the dermal tissues is a challenging complication of radiotherapy, since mechanism of action is not fully understood and there are only few available treatments. The canonical wnt/β-catenin signaling athway plays an important role in fibrotic reaction as well as epithelial-to-mesenchymal transition. We verified whether that inhibition of wnt/β-catenin signaling pathway with sLRP6E1E2 that is binding to extracellular wnt ligands would ameliorate radiation-induced fibrosis both in vitro and in vivo. Radiation with a single dose of 2Gy not only facilitated fibrotic reaction in cultured human dermal fibroblasts via activated wnt/β-catenin pathway, but is also responsible for epithelial to mesenchymal transition of cultured keratinocytes, developing collagen-producing mesenchymal cells. sLRP6E1E2-expressing adenovirus treatment exerted anti-fibrotic actions in irradiated cultured dermal fibroblasts and keratinocytes. In a mouse model, a single fraction of 15Gy was delivered to the dorsal skin of each mouse. Thirty mice were randomized into three groups: PBS, control adenovirus (dE1-k35) and decoy wnt receptor-expressing adenovirus (dE1-k35/sLRP6E1E2). The mice were observed for 16 weeks, and there was no significantly different gross change observed in comparison with controls. In semi-quantitative analysis with Masson’s trichrome staining, excessive collagen deposition was suppressed by sLRP6E1E2-expressing adenovirus treatment. These results support that modulation of wnt/β-catenin pathway has the potential to decrease the severity of radiation-induced dermal fibrosis.