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Anti-fibrotic mode of action and efficacy of TXA127 as disease modifying therapy of recessive dystrophic epidermolysis bullosa (RDEB): a preclinical study

Completed
Project leadDr. Alexander Nyström
Organisation University of Freiburg Medical Center
Partner organizations & collaboratorsProf. Leena Bruckner-Tuderman at University of Freiburg, Medical Center, Germany
Project budgetEUR 194,250.00
Start date / Duration01. May 2017 / 12 months
Funder(s) / Co-Funder(s) DEBRA Austria
Research area Skin cancer & fibrosis

Project details

Short lay summary

A major complication of recessive dystrophic epidermolysis bullosa (RDEB) is progressive scarring, fibrosis and formation of mitten deformities of hands and feet. These changes are also connected to an increased risk of developing skin cancer. This project aims to evaluate a novel therapy to reduce scarring and fibrosis and to delay formation of mitten deformities of hands and feet. The compound that we are evaluating is Ang-(1-7), which is naturally occurring in our bodies.

 

Scientific summary

RDEB is a skin fragility disorder caused by genetic deficiency of collagen VII. Progressive soft tissue scarring occurring subsequent to skin blistering is greatly debilitating. Limiting fibrosis could significantly increase functionality and improve the quality of life of patients. Preliminary studies have revealed that TXA127, a pharmaceutical formulation of the naturally occurring peptide, angiotensin (1-7) or Ang(1-7), reduces fibrosis in an RDEB mouse model. TXA127 is an attractive drug candidate because it is well-tolerated and is Phase II ready. We propose to carefully evaluate the therapeutic potential of TXA127 in RDEB. We will perform a three-armed preclinical animal study, delineate TXA127 signaling mechanisms using genetic models and establish relevance for treatment of patients using human skin cells. The aim of the study is to generate data that serves as the basis for a clinical trial evaluating the safety and efficacy of TXA127 for treatment of RDEB.

What did this project achieve?

We have treated mice that have mutations in the same gene as people with RDEB and display manifestations that are similar to the human disease. In such RDEB model mice Ang-(1-7) was efficient in reducing the formation of mitten deformities, thus extending the functionality of the paws.

We have also performed studies to understand how these effects are reached in the skin and we have identified two receptors responsible for mediating the effect of Ang-(1-7). Furthermore, using skin cells isolated from people with RDEB we have shown that of Ang-(1-7) also likely reduces scarring and fibrosis in humans.

Our studies have revealed that a lower dose of Ang-(1-7) seems to be more efficient in reducing scarring and fibrosis in RDEB. This is an important finding that will help the development of optimal dosing of Ang-(1-7),

Together our study has provided first evidence that Ang(1-7) could be a potentially new, safe and efficient therapy to reduce scarring and also the aggressiveness of cancer in RDEB. It has also identified new questions that need answer before Ang-(1-7) can be developed into a drug for treatment of RDEB.


Keywords

Nyström
Bruckner-Tuderman
RDEB
preclinical
TXA127
University of Freiburg
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