Proteins involved in activating genes may contribute to RDEB fibrosis
Blocking abnormal histone modification with valproic acid reduced scarring
An altered modification of proteins involved in controlling gene activity, called histones, may contribute to how severe the buildup of excessive scar tissue is in recessive dystrophic epidermolysis bullosa (RDEB), a study suggests.
Blocking abnormal histone modification with the approved medicine valproic acid reduced the signs of scarring, or fibrosis in skin and tissue samples from RDEB patients and in an RDEB mouse model.
The findings suggest that medicines like valproic acid may be “rapidly repurposed for the treatment of RDEB,” the researchers wrote in “Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa,” which was published in the British Journal of Dermatology.
RDEB is caused by mutations in the COL7A1 gene, which leads to a lack of collagen type VII, a connective tissue protein. Without it, skin becomes fragile and easily blisters. Chronic skin wounds often cause inflammation and fibrosis, which can progress to aggressive forms of skin cancer.
As a recessive disease, patients must have inherited two copies of disease-causing mutations, one from each parent. Despite inheriting the same mutations, however, some siblings with recessive disease are seen with a wide range of symptoms, which suggests that epigenetic modifications may contribute to disease severity. Epigenetics refers to cellular processes that control gene activity without altering a gene’s DNA sequence.
Role of epigenetic modifications in RDEB
One epigenetic mechanism occurs through the modification of histones, which are positively charged proteins that condense and package negatively charged DNA. To make DNA more accessible for gene expression, histones are modified with a type of chemical group called acetyl, reducing the positive charge and weakening the interaction between histones and DNA.
Histone acetylases are enzymes that add acetyl groups to histones, which increases gene activity, while histone deacetylases are enzymes that remove acetyl groups, shutting down gene expression.
A research team in Italy, Switzerland and Germany investigated the role of histone acetylation in RDEB skin and tested whether molecules that block histone deacetylases might act as therapies for fibrosis in RDEB mice.
First, histone acetylation was found to be reduced in skin samples from 11 RDEB patients compared with those from five non-RDEB people. Similar results were found in isolated fibroblasts, the connective tissue cell type that produces collagen, “suggesting that global acetylation activity is affected in RDEB skin,” the researchers wrote.
RDEB fibroblasts were treated with two approved medicines that inhibit the activity of histone deacetylases (HDACi), givinostat and valproic acid (VPA). Givinostat, sold as Duvyzat, is indicated for Duchenne muscular dystrophy and valproic acid is primarily used to treat epilepsy, bipolar disorder, and migraine headaches.
Exposing RDEB fibroblasts to these two molecules reduced the signs of fibrosis, including a weakened ability of fibroblasts to contract and lower levels of TGF-beta1, a molecule that drives RDEB-associated fibrosis. The treatment also lowered the percentage of actively growing RDEB fibroblasts.
In a RDEB mouse model, histone acetylation was also reduced in skin samples. Treatment with VPA, administered via food, significantly increased skin histone acetylation levels and reduced disease severity in the eyes and paws over untreated mice.
Skin samples from RDEB mice treated with VPA had reduced signs of fibrosis, including relaxed collagen bundles, lower levels of TGF-beta1, and decreased tenascin-C and alpha-SMA, two other markers of fibrosis. Eye and tongue tissue showed similar results. VPA also normalized the activity of genes involved in protein production and immune function in the skin of RDEB mice.
“Dysregulated histone acetylation contributes to RDEB pathogenesis [disease processes] by facilitating the progression of fibrosis,” the researchers said. “Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.”
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