Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation rem...

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Bibliographic Details
Published in:EMBO molecular medicine 2015-09, Vol.7 (9), p.1211-1228
Main Authors: Nyström, Alexander, Thriene, Kerstin, Mittapalli, Venugopal, Kern, Johannes S, Kiritsi, Dimitra, Dengjel, Jörn, Bruckner‐Tuderman, Leena
Format: Article
Language:English
Subjects:
Animals
Collagen
collagen VII
Data analysis
Disease
Disease Models, Animal
Dystrophic epidermolysis bullosa
Epidermolysis bullosa
Epidermolysis Bullosa Dystrophica - drug therapy
Epidermolysis Bullosa Dystrophica - pathology
Fibrosis
Genotype & phenotype
Immunoglobulins
Immunologic Factors - therapeutic use
Inflammation - pathology
losartan
Losartan - therapeutic use
Marfan syndrome
Mice
Proteins
Proteome - analysis
Proteomics
Skin
Skin diseases
TGF‐β
Transforming Growth Factor beta - antagonists & inhibitors
Treatment Outcome
Tumor necrosis factor
Writing
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Summary:Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)—a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence‐based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF‐β activity is elevated in injured RDEB skin, we targeted TGF‐β activity with losartan in a preclinical setting. Long‐term treatment of RDEB mice efficiently reduced TGF‐β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan‐ vs. vehicle‐treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF‐α and IL‐6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF‐β‐mediated inflammation, and matrix remodeling. Inhibition of TGF‐β activity limits these unwanted outcomes and thereby substantially ameliorates long‐term symptoms. Synopsis Targeting the secondary consequences of collagen VII loss with FDA‐approved drug losartan ameliorates recessive dystrophic epidermolysis bullosa (RDEB) in a mouse model. Modulation of disease mechanisms by repurposing approved drugs is an attractive approach to manage connective tissue disorders. In RDEB, disease progression is driven by repeated cycles of tissue damage, inflammation, and TGF‐β‐mediated matrix remodeling. Reduction of TGF‐β activity by targeting the angiotensin–renin system with losartan effectively slows down disease progression in a preclinical setting. Treatment of RDEB mice with 0.6 g/l losartan in drinking water reduced digit fusion and prolonged functionality of forepaws for up to 30 weeks. RDEB can be significantly ameliorated without correcting the underlying genetic defect. Targeting the secondary consequences of collagen VII loss with FDA‐approved drug losartan ameliorates recessive dystrophic epidermolysis bullosa (RDEB) in a mouse model.
ISSN:1757-4676
1757-4684
DOI:10.15252/emmm.201505061