Methotrexate Might Help in Skin Healing in RDEB, Study Suggests
More than 2,000 transcripts — RNA molecules that derive from DNA and carry instructions for protein production — were found to be differentially produced between intact skin and wounds in people with recessive dystrophic epidermolysis bullosa (RDEB).
Based on these findings, computer simulations identified the prescription medication methotrexate as a therapy that might promote wound healing in RDEB.
Methotrexate is used to treat the skin disease psoriasis, rheumatoid arthritis, and certain inflammatory conditions and cancers.
The study, “Transcriptomic profiling of recessive dystrophic epidermolysis bullosa wounded skin highlights drug repurposing opportunities to improve wound healing,” was published in the journal Experimental Dermatology.
RDEB is an inherited blistering skin condition caused by mutations in the COL7A1 gene that encodes for type VII collagen, an important component of anchoring fibrils — large structural elements that hold the skin together.
In patients with the inherited disease, the physiological processes required for tissue repair are affected, leading to delayed wound healing, inflammation, scarring, and an increased risk of squamous cell carcinoma (SCC), a common type of skin cancer. There currently is no cure, and treatments that can improve and speed up wound healing are lacking.
Now, a group of scientists in the U.K., the U.S., and Indonesia hypothesized that, in RDEB patients, the expression (activity) of certain genes would be different in wounded skin sections as compared with intact skin. If so, the researchers could then look for compounds to revert the abnormal expression profiles in wounds. The goal was to find therapies that might be repurposed for treating wounds in RDEB.
To that end, biopsies were collected from six RDEB patients, ages 25 to 52. The biopsies were taken from skin next to a chronic wound — defined as being present for at least six weeks with no signs of healing — as well as from normal-appearing skin. Six healthy individuals also provided skin biopsies and served as controls. Patients and controls were matched on sex, age, ethnicity, body site, and biopsy time.
Transcriptome profiling was used to identify which genes were turned “on” or “off,” by detecting the full range of RNA molecules in each sample. A total of 2,388 transcripts were differentially expressed between wounded and intact skin from EB patients, while 2,685 transcripts were differentially expressed between wounds and skin samples from the healthy participants.
Computer analysis revealed that the dysregulated genes in wounds were associated with a signaling pathway called JAK/STAT, Toll-like receptors, which are typically found on immune cells, and interactions between cytokines — signaling molecules that mediate immune responses. According to the researchers, these are “key activating events in RDEB wounds”.
Next, the team sought to identify molecules with the potential ability to oppose the differentiated genes in wounded RDEB skin. They used L1000FWD, an online application that allows the visualization of more than 16,000 compound-induced gene expression signatures. Using their previously identified datasets of differentially expressed genes, a total of 50 compounds were predicted to stimulate wound healing in RDEB.
Four of the 10 best compounds were found to be commercially available medications: simvastatin, used to lower cholesterol; anafranil, an antidepressant; fulvestrant, a breast cancer therapy; and methotrexate.
Among these, the investigators highlighted methotrexate, an approved therapy for the skin conditions psoriasis and atopic eczema, and generally safe, even for children.
As such, “methotrexate might merit testing in animal models of RDEB or in patients with RDEB to see whether the in silico [computer] predictions might be paralleled by changes in skin transcriptomes that lead to greater skin integrity and perhaps better wound healing,” the team wrote.
“Overall, this study provides insight into the molecular profiles of RDEB wounds and underscores the possible clinical value of reverse transcriptomics data analysis in RDEB, and the potential of this approach in discovering or repurposing drugs for other diseases,” they concluded.