Anti-fibrotic therapeutic potential of histone deacetylase inhibitors (HDACi) for RDEBOngoing
|Project lead||Dr. Daniele Castiglia|
|Organisation||Istituto Dermopatico dell' Immacolata - IRCCS|
|Project budget||EUR 160,000.00|
|Start date / Duration||01. Jul 2019 / 36 months|
|Funder(s) / Co-Funder(s)||DEBRA UK, DEBRA Austria|
|Research area||Skin cancer & fibrosis, EB genetics, epigenetics & biology|
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.
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.
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.