Anti-fibrotic therapeutic potential of histone deacetylase inhibitors (HDACi) for RDEB (Castiglia 1)
Completed| Project lead | Dr Daniele Castiglia |
| Organisation | Istituto Dermopatico dell' Immacolata - IRCCS, Rome, ITALY |
| Project budget | EUR 160,000.00 + 18 months time only extension |
| Start date / Duration | 01. Jul 2019 / 47 months |
| Funder(s) / Co-Funder(s) | DEBRA UK, DEBRA Austria, EB MSAP/EBEP Recommended |
| Research area | Skin cancer & fibrosis, EB genetics, epigenetics & biology |
Publications related to the projects
Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosaProject details
Short lay summary
A significant concern in RDEB is the presence of chronic inflammation and progressive fibrosis, which may cause severe disease manifestations and lead to cancer. TGF-β, a protein that activates many cell responses, triggers molecular signals responsible for RDEB skin fibrosis onset and progression. Mutations in the gene encoding the skin protein collagen VII are the primary cause of RDEB. However, other genes can worsen or improve the disease course depending on whether they are more or less active. Epigenetic changes are heritable modifications that modulate gene activation without changing the DNA sequence. Among these modifications, histone acetylation seems to play an important role in the development of dermal fibrosis. Reduced histone acetylation is associated with pro-inflammatory and pro-fibrotic changes in the skin microenvironment. It is, therefore, reasonable to think that controlling this process may help revert fibrosis. This team found that two small drugs targeting histone acetylation can reduce RDEB fibroblast fibrosis and TGF-β activity. The first aim of this project is, therefore, to test their ability to lessen or mitigate disease manifestations in an RDEB mouse model. The second aim is to characterize their mechanism of action in cultured human RDEB fibroblasts.
Scientific summary
Experimental findings indicate that epigenetic modifications influence RDEB disease severity by driving stromal cells towards a pro-fibrotic phenotype in response to injuries. We will investigate the capability of epidrugs that modulate gene expression by targeting histone modifications to counteract the pro-fibrotic memory of RDEB skin fibroblasts and the disease course in RDEB mice. Two histone deacetylase inhibitors, one already in phase III trial and the other approved for clinical treatments, both known to have anti-fibrotic effects in vitro and in vivo, will be tested. Positive results will foster clinical translation as repurposing drugs to counteract RDEB fibrosis.
Strategic relevance
Fibrosis and chronic inflammation are two of the most severe consequences of RDEB. Not only do they cause disability and pain, but they also create an environment in which squamous cell carcinomas occur. Reducing fibrosis early on during the progression of the disease improves not only the immediate quality of life but also the long-term life prospects for people with RDEB and is, therefore, a strategic priority. Because these drugs are in clinical use, it is expected that, if successful, they would benefit from a shorter path to clinical translation.
What did this project achieve?
The aim of this project was to investigate the possibility of targeting epigenetic modifications that influence the pro-fibrotic memory of RDEB. The results showed that the levels of one type of histone modification, acetylation, are decreased in RDEB skin and cultured skin fibroblasts. When histone acetylation levels in RDEB fibroblasts were restored with drugs that inhibit deacetylation, givinostat and valproic acid, these cells responded by reducing their profibrotic phenotype. The therapeutic antifibrotic potential of these inhibitors was validated in col7a1 hypomorphic mice, a preclinical model of RDEB. Valproic acid was able to reduce the severity of the disease, for example by limiting the development of paw and eye abnormalities, and that this effect was associated with inhibition of fibrosis.
These findings suggest that dysregulated histone acetylation affects molecular pathways that contribute to fibrosis in RDEB. They also provide preclinical proof of concept for histone deacetylase inhibitors, in particular valproic acid, in the treatment of fibrosis in RDEB. As this drug is used to treat other diseases, our data pave the way for its repurposing to accelerate clinical development in RDEB.