Recessive dystrophic EB: Mechanisms of fibrosis and its prevention with Losartan in vivo (Bruckner-Tuderman 4 + Ext)
Completed| Project lead | Prof Leena Bruckner-Tuderman |
| Organisation | University of Freiburg Medical Center, Freiburg, GERMANY |
| Project budget | EUR 278,060.00 + EUR 106,765.00 (Extension) |
| Start date / Duration | 01. Apr 2012 / 48 months |
| Funder(s) / Co-Funder(s) | DEBRA Austria, EB MSAP/EBEP Recommended |
| Research area | Symptom prevention & relief |
Project details
Short lay summary
This project elucidates possibilities to attenuate scarring and fibrosis in recessive dystrophic EB (RDEB). The goal is to test and identify small molecules as pharmacologic “anti-fibrosis” agents, which prevent progressive scarring and improve the texture of the skin. The hope is that softer and less scarred skin would not be prone to develop squamous cell carcinoma.
Our investigations are experimental and pre-clinical studies using mouse models (the so called collagen VII hypomorphic mouse, or RDEB mouse) and skin cells. The first goal is to understand how a “pro-fibrotic” molecule, the transforming growth factor-ß (TGF-ß), acts in RDEB skin. This factor drives fibrotic changes in many diseases, but it is known that the effects are tissue- and disease-specific. Therefore, first, the mode of action of TGF-ß in RDEB will have to be carefully mapped. Thereafter, TGF-ß inhibitors can be tested and their mechanisms of action elucidated. Particular attention will be paid to losartan, an approved drug for the treatment of high blood pressure. Losartan has also anti-fibrotic effects and has been successfully used to prevent fibrotic changes in other hereditary diseases, such as Marfan syndrome of muscular dystrophies. These observations encourage us to hypothesize that losartan may have beneficial effects in RDEB, too.
What did this project achieve?
In this project we elucidated disease mechanisms in recessive DEB (RDEB) and showed that not only the loss of collagen VII, but also many other factors contribute to the progression of RDEB. Based on our own research and results of other investigators we know that a growth factor named TGFβ (transforming growth factor beta) plays a major part in RDEB disease progression. Therefore, we evaluated the effect of a drug that reduces TGFβ activity, losartan, on RDEB disease progression.
Our studies in RDEB mice clearly showed that losartan treatment reduced scarring and development of mitten-like deformities. No obvious adverse effects were noticed in the mice receiving the drug. Microscopic, molecular analyses and sophisticated proteomics analyses supported the clinical findings. Losartan clearly lowered fibrosis and ameliorated stiffened tissue.
Our studies also revealed why people with RDEB develop aggressive skin cancer. The structural instability of RDEB skin, combined with repeated blistering and wounding, and altered TGFβ cause skin stiffening. This, in turn. Increases skin cancer progression. In cell culture, inhibitors of TGFβ reduced tissue stiffness and limited cancer invasion. The effect of losartan on skin cancer is now being tested in the RDEB mouse model.
From the outcome of these studies we believe that losartan or other drugs that interfere with TGFβ will be effective to reduce fibrosis, and potentially also skin cancer, in RDEB. The drugs will not cure but they will slow down disease progression and thereby ameliorate the symptoms and improve quality of life of people with RDEB. Based on the positive findings of this project and the safety of losartan as a drug, we will perform a clinical trial with losartan treatment of people with RDEB, which we hope to start in the fall of this year.