Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a mucocutaneous blistering disease due to type VII collagen gene mutations. Transforming growth factor-β (TGF-β)-dependent fibrosis is responsible for severe RDEB complications. Reduced histone acetylation is a hallmark of fibrosis in pathologies affecting organs other than skin, where inhibition of histone deacetylses (HDACs) proved effective in reverting fibrosis. Here, HDAC inhibitor (HDACi) ability to counteract RDEB progression was investigated. We found that histone acetylation is decreased in RDEB skin and fibroblasts. Treatment with two HDACis, valproic acid (VPA) and Givinostat, counteracts RDEB fibroblast fibrotic traits, including contractility, α-smooth muscle actin expression, TGF-β1 release, and proliferation. Moreover, systemic VPA administration mitigates severe manifestations (corneal opacification and digit loss) in a RDEB mouse model. This effect associates with inhibition of skin fibrosis (presence of subcutaneous fat, thinner collagen bundles, decreased expression of fibrotic markers). Proteomic analysis of mouse skin revealed that VPA treatment decreases expression of genes involved in protein synthesis and increases levels of proteins with role in immune response. These findings highlight epigenetic changes as contributing to RDEB pathogenesis and disclose molecular mechanisms leading to skin fibrosis. Treatment with HDACi may represent a disease modifier therapeutic approach for RDEB and other skin fibrotic disorders.