Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin blistering disease due to mutations in the COL7A1 gene coding for collagen VII. In RDEB, unremitting skin blistering leads to chronic wounds, inflammation and fibrosis; these features are responsible for more severe disease complications, such as mitten deformities and squamous cell cancer. Recent studies highlighted the role of TGF- pathway in modifying RDEB severity, and our findings showed that the proteoglycan decorin (DCN), a biological TGF-β inhibitor, can influence disease outcome by counteracting TGF-β profibrotic and proinflammatory activity. In this study, we evaluated DCN potential in improving disease manifestations in col7a1 hypomorphic mice, a model of severe RDEB. Newborn mice were treated with a lentivirus expressing DCN (LV-DCN), or a control lentivirus (LV-CTRL) or saline solution, by intraperitoneal injection. DCN overexpression in the skin of LV-DCN-treated mice associated with increased median survival time (LV-DCN, 19 days; LV-CTRL, 12 days; saline, 10 days) and survival rate (LV-DCN, 40.5%; LV-CTRL, 20.4%; saline, 28.3%; p<0.05 LV-DCN vs LV-CTRL and vs saline) as compared to control treatments, at the endpoint of 12 weeks of age. Digit length was increased only in LV-DCN-treated mice (p=0.03, right limb; 0.01, left limb), and percentage of mice with digit loss was reduced following LV-DCN treatment (LV-DCN, 35.7%; LV-CTRL, 77.8%; saline, 92.7%; p=0.005 LV-DCN vs saline). The expression of markers of fibrosis (tenascin-C and α-smooth muscle actin), inflammation (CD11b) and TGF-β signaling activation (p-SMAD2) was also significantly reduced in the skin of LV-DCN treated mice. By contrasting TGF--driven fibrosis, DCN is thus able to ameliorate disease symptoms and survival of hypomorphic mice.

Decorin Increases Survival and Ameliorates Disease Phenotype of Col7a1 Hypomorphic Mice