Research presented at the European Academy of Dermatology and Venereology in Prague, Czech Republic, suggests that inhibition of the SMAD protein may be a viable therapeutic target in scleroderma patients.
This finding builds on previous research by presenter and lead researcher Donal O'Kane (Queens University Belfast, UK) and colleagues showing that epidermal to mesenchymal transition (EMT) occurs in the skin of scleroderma patients. This is most likely induced by high levels of the inflammatory cytokines transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α in sclerodermatous skin, and contributes directly to cutaneous fibrosis.
In the current study, O'Kane and team showed that SMAD inhibition weakens or reverses EMT in a normal human epidermal keratinocyte cell line. EMT was induced in the cells by the introduction of high levels of TGF-β and TNF-α to mimic conditions present in sclerodermatous human skin.
These findings could prove a real breakthrough for scleroderma patients, as currently available treatments for scleroderma are limited and often ineffective.
"At the minute because no treatments work effectively in clinical practice my feeling is that that's because they focus on fibrosis in the dermis as opposed to what predates that," O'Kane told medwireNews.
"The novel part of this EMT is we think that's before the fibrotic phase," he added, "so it gives a total new approach to the treatment of fibrotic disease and potentially will raise a lot more treatments as well."
The signaling pathways involved in the EMT in scleroderma are targeted by several drugs that are already on the market for other indications including ACE inhibitors, which target the SMAD pathway, statins, and the allergy drug tranilast.
O'Kane and colleagues are currently trialing potential inhibitors of the SMAD pathway and hope to carry out mouse studies and clinical trials in humans in the near future. O'Kane explained that as the inhibitors they are focusing already have acceptable safety profiles in patients they hope that human and animal trials can be run concurrently.
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