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Repurposing Drugs to Treat Fibrosis Associated with RDEB

Project Title: Anti-Fibrotic Therapeutic potential of Histone Deacetylase Inhibitors (HDACi) for Recessive Dystrophic Epidermolysis Bullosa

Investigator: Dr Daniele Castiglia, Molecular Geneticist

Institution: Istituto Dermopatico dell'Immacolata, IRCCS

Start Date: for 2 years

Grant amount:  €160,000 - Co funded with DEBRA Austria

Lay Summary

About this research and why it is important: 

Observations suggest that genetic mistakes leading to a lack of collagen VII are not the only cause of disease severity in recessive dystrophic epidermolysis bullosa (RDEB). Other genes, called ‘modifier genes’, (genes that influence or change the expression of another gene), can also improve or worsen disease depending on their activity. These modifier genes and their effects could be targeted therapeutically (to try and find a treatment) to reduce symptoms and potentially change the course of the disease. This could be done in addition to targeting the original genetic mistake.

Heritable or “epigenetic” changes are those which modify the activation of genes without altering our DNA or genetic sequence. They may be responsible for differences in modifier genes.

A major concern in RDEB is the presence of inflammation and progressive fibrosis of skin and mucosae (oral cavity, oesophagus, etc.) which cause severe problems, such as mitten deformities (fusion of the fingers), strictures (narrowing of the oesophagus) and EB associated cancer. Closely linked to this, a protein called TGF-β that activates many cell responses, triggers molecular signals responsible for RDEB skin fibrosis onset and progression.

Experimental findings indicate that epigenetic changes may influence RDEB disease severity by encouraging cells towards fibrosis when the skin is injured and this could be a target for treatment. This group has found that small drugs targeting one type of epigenetic change called histone acetylation (molecules that impact on how the DNA is folded rather than its genetic make-up) can reduce RDEB fibrosis and activity of TGF-β.

How this research will take place and what it might lead to:

This proposal is aimed at testing the therapeutic or treatment potential of two “epigenetic” drugs, already used clinically in other fibrotic disorders, in lessening and delaying complications associated with disease in an RDEB laboratory (animal) model.

 

DNA (red string) is wrapped around histones (blue beads). Compacted DNA associates with inactive genes while a histone modification, called acetylation (Ac) allows DNA to be less condensed, a status that usually favour gene activation. By inhibiting histone deacetylases (HDACs), epigenetic drugs, like givinostat and valproic acid, favour an increase of histone acetylation, thus promoting gene expression. Modifier genes with anti-fibrotic effects may become activated. 

The group will investigate the capability of these “epidrugs” to modulate gene expression to help counteract fibrosis in RDEB skin. The two drugs that will be tested in this piece of research are Givinostat, a histone deacetylation inhibitor (HDACi) which is in clinical trials for a number of conditions, and an approved drug called Valproic acid which is licensed for other medical conditions, both known to have antifibrotic effects shown in previous research. Results from this research will hopefully lead to further clinical trials possibly repurposing or reusing drugs to counteract RDEB fibrosis and the problems associated with it.

Investigator Biography

Castiglia

Dr. Daniele Castiglia is a molecular geneticist and Director of the laboratory of molecular and cell biology at Istituto Dermopatico dell’Immacolata, IDI-IRCCS in Rome. He has over 20 years working in the field of EB and other genodermatoses acquiring specific skills relating to molecular basis and genotype-phenotype correlation. His research activity is focused on cellular and molecular mechanisms of EB complications to reveal novel targets for disease-modifying therapeutic approaches.