This project will provide evidence for the repurposing of two existing medicines to treat and reduce the scarring in RDEB that leads to loss and fusion of fingers and symptoms affecting eyes and other parts of the body.

Dr Daniele Castiglia is Director of the Laboratory of Molecular and Cell Biology at Istituto Dermopatico dell’Immacolata, IDI-IRCCS in Rome, Italy. His research aims to generate evidence that existing anti-fibrotic medications can reduce scarring (fibrosis) in RDEB. Changes in the COL7A1 gene mean that people with RDEB don’t have working collagen protein in their skin. However, differences in the amounts or activity of other proteins may make their symptoms more or less severe. If the levels of these other proteins can be altered with existing medications, the scarring that leads to loss and fusion of fingers and symptoms affecting eyes and other parts of the body may be reduced.

 

Contents:

• Project summary (top of page)
• About our funding
• Final progress summary (2023)
• About our researchers
• Why this research is important
• Researcher's abstract
• Researcher's progress update (2022)
• Researcher's final update (2023)

 

About our funding:

Research leader	Dr Daniele Castiglia
Institution	Istituto Dermopatico dell'Immacolata, IRCCS, Italy
Type of EB	RDEB
Patient involvement	None
Funding amount	€160,000 (co-funded with DEBRA Austria)
Project length	3 years (extended due to Covid)
Start date	December 2018
DEBRA internal ID	Castiglia1

 

Final progress summary (2023):

Researchers found that two drugs (givinostat and valproic acid) helped to make RDEB skin cells grown in the laboratory healthier. Valproic acid was also able to reduce RDEB symptoms that affect eyes, hair and skin. Valproic acid is approved and widely used for other conditions. This work provides evidence to support it being repurposed to slow the onset and progression of symptoms in people living with RDEB.

Researchers published a review of their work on skin fibrosis in 2021.

 

About our researchers:

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.

 

Why this research is important:

Our proposal is aimed at testing the therapeutic potential of two epigenetic drugs, already used at clinical levels in other fibrotic disorders.

Dr Daniele Castiglia

 

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Researcher’s abstract:

Grant Title: Anti-fibrotic therapeutic potential of histone deacetylase inhibitors (HDACi) for recessive dystrophic epidermolysis bullosa.

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.

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 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.

 

Researcher’s progress update:

Many observations attest that collagen VII amount is not the only cause of disease severity in recessive dystrophic epidermolysis bullosa (RDEB) patients; other genes, called modifier genes, can improve or worsen disease manifestations depending on whether they are more or less active. Therefore, modifier genes and their effects could be therapeutically targeted to reduce symptoms and ameliorate disease course.

A major concern in RDEB is the presence of inflammation and progressive fibrosis (induration) of skin and mucosae (oral cavity, oesophagus, etc.) which cause severe disease manifestations, such as mitten deformities, strictures and cancer. TGF-β, a protein that activates many cell responses, triggers molecular signals responsible for RDEB skin fibrosis onset and progression.

Heritable changes which modify the activation of genes without altering our DNA sequence are known as epigenetic changes. They may be responsible for differences in modifier genes and in clinical manifestations in RDEB individuals.

We found that small drugs targeting a major epigenetic change, histone acetylation, can reduce RDEB fibroblast fibrosis and TGF-β activity.

Our proposal is aimed at testing the therapeutic potential of two epigenetic drugs, already used at clinical levels in other fibrotic disorders, in lessening and delaying disease manifestations of a RDEB model. We found that one of the two drugs is able to counteract skin fibrosis and disease progression by reducing severe manifestations such as digit loss and corneal scarring. Studies are ongoing to explore the molecular and cellular effects of drug administration. (From 2022 progress report.)

 

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Researcher’s final update (2023):

Many observations attest that collagen VII amount is not the only cause of disease severity in recessive dystrophic epidermolysis bullosa (RDEB) patients; other genes, called “modifier genes”, can improve or worsen disease manifestations depending on whether they are more or less active. Therefore, modifier genes and their regulation and activity could be therapeutically targeted to reduce symptoms and ameliorate disease course. For example, changes in gene expression of decorin and TGF-β, two molecules present in the skin microenvironment, have been reported in RDEB as associated to disease severity variability, and two studies have demonstrated that delivering decorin in skin affected by RDEB ameliorates  disease phenotype by counteracting TGF-β activity, the excess of which triggers molecular signals responsible for skin fibrosis onset and progression. Indeed, a major concern in RDEB is the presence of inflammation and progressive fibrosis (induration) of skin and mucosae (oral cavity, oesophagus) which cause severe disease manifestations, such as mitten deformities, strictures and cancer. Heritable changes which modify the activity of genes without altering DNA sequence are known as epigenetic changes. They may be responsible for differences in modifier genes and clinical manifestations in RDEB individuals. The results of our work demonstrate that a major epigenetic change, known as histone acetylation, is altered in RDEB skin. Besides, we identified two “epigenetic drugs” (givinostat and valproic acid) that target histone acetylation and found that they can both counteract the profibrotic behavior of cultured fibroblasts from RDEB individuals, including mitigation of TGF-β activity. Our proposal was then aimed at testing the ability of these two drugs, already tested in other fibrotic disorders at preclinical level, in lessening and delaying RDEB disease manifestations in a RDEB mouse model. We found that valproic acid was able to counteract skin fibrosis and to efficiently mitigate disease complications, such as digit loss and corneal scarring. This drug acts by counteracting TGF-β-dependent effects, (abnormal matrix deposition, increased cell proliferation, activation of profibrotic and protumorigenic signaling pathways). As valproic acid is approved and widely used in clinical practice for non-skin conditions, it could be repurposed to counteract the onset and progression of fibrosis also in RDEB individuals. (From 2023 final report.)

 

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Image credit: Luong LD SA F2, adapted from Luong, P. Basic Principles of Genetics, Connexions Web site. [http://cnx.org/content/m26565/1.1/] (2009). Licensed under the Creative Commons Attribution 3.0 License.