Multimodality targeting of chronic inflammation and fibrosis in epidermolysis bullosaOngoing
|Project lead||Prof. Andrew South (Prof. Ulrich Rodeck originally submitted the proposal)|
|Organisation||Thomas Jefferson University, Jefferson Medical College|
|Partner organizations & collaborators||Dr. Alexander Nyström (Co-Applicant) at University of Freiburg, Prof. Joel Rosenbloom (Collaborator) at Thomas Jefferson University|
|Project budget||EUR 126,132.38|
|Start date / Duration||06. Jan 2021 / 24 months|
|Funder(s) / Co-Funder(s)||DEBRA Ireland, DEBRA Austria|
|Research area||Symptom prevention & relief|
Short lay summary
This application seeks to delay development and reduce severity of chronic inflammation and fibrosis associated with blistering genodermatoses including RDEB. We will test the hypothesis that 3 different drug classes, when combined, will synergize in reducing chronic inflammation and fibrosis development in mouse models of intermediate junctional epidermolysis bullosa (formerly non-Herlitz JEB) and recessive dystrophic epidermolysis bullosa (RDEB) that are established in our laboratories.
In this application we will test the utility of drug combinations which target signaling pathways and molecular mechanisms driving chronic inflammation and fibrosis in epidermolysis bullosa. The main intent of the proposed work is to test synergy of these agents in appropriate animal models.
We have observed that three distinct drug classes reduce the severity of chronic inflammation and/or fibrosis in diverse experimental settings. These compounds are the kinase inhibitor trametinib, which selectively targets the mitogen-activated protein kinase MEK, the angiotensin receptor 1 (AT1R) inhibitor losartan and the synthetic triterpenoid RTA408 which exerts cytoprotective and anti-inflammatory effects including Nrf2-dependent expression of antioxidant enzymes and inhibition of IL- 1beta processing. These pathways may be of relevance to chronic wound healing and inflammation in RDEB.
Trametinib and losartan are FDA-approved for other applications whereas RTA408 is currently in clinical development for indications other than blistering diseases. Thus far, the three compounds have been used as single agents only. The main goal of this application is to test, in the Lambc(jeb) and collagen VII hypomorphic EB models, whether combining the three drugs will improve therapeutic efficacy while reducing the risk of adverse events associated with the long-term use for prevention and treatment of fibrosis.
New drug development is a time-consuming and high-cost process. Drug repurposing generally offers various advantages over developing an entirely new drug for a given indication : reduced risk of failure, shorter development time frame and lower costs. Approved and clinical drugs may have identified bioactivities, good pharmacokinetic characteristics and safety profiles, which render them suitable for drug repurposing. Trametinib and losartan are FDA-approved for other applications whereas RTA408 is currently in clinical development for indications other than blistering diseases. The use of drugs that are approved or already in clinical testing may render the path to clinical development and use in EB easier in the future.
Find more on DEBRA Ireland's website.