Targeting long-term inflammation and scarring in EB from three different angles

• Primary Researcher: Prof Andrew South (on behalf of Prof Ulrich Rodeck on his passing)
• Institution: Thomas Jefferson University, Philadelphia, USA
• Type of EB: RDEB
• Funding amount: €126,133 co-funded with DEBRA Austria
• Project length: 3 years

Due in 2024.

Researchers

Prof Andrew South is a professor at Thomas Jefferson University, Philadelphia, USA. His laboratory focuses primarily on cutaneous SCC (cSCC) which is the most frequent skin cancer with malignant potential and contributes to greater than 1 in 4 skin cancer deaths in Caucasian populations. Patient groups with a high propensity to develop these tumors face a significant risk of mortality. One such group is the genetic skin 3 blistering condition recessive dystrophic epidermolysis bullosa (RDEB). His laboratory has a long-standing interest in trying to understand why mutations in the single COL7A1 gene lead to frequent and multiple life-threatening skin cancers.

Dr Alexander Nystrom is a group leader in the Department of Dermatology, Medical Centre at the University of Freiburg, Germany. His research group’s translational research is focused on dissecting the roles of the extracellular matrix in skin during homeostasis, normal and pathological wound healing, immune surveillance and in cancer. They use this knowledge to develop new therapy approaches for treatment of bacterial infections, fibrosis and squamous cell carcinoma. A specific interest is on improving the understanding of disease mechanisms in the genetic skin blistering disease, dystrophic epidermolysis bullosa, toward developing safe, efficacious targeted-treatment

Grant Title: Multimodality targeting of chronic inflammation and fibrosis in epidermolysis bullosa

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.

Due 2024.