Recessive dystrophic epidermolysis bullosa (RDEB) is a low prevalence genetic disease characterized by extreme fragility of the skin and mucous membranes that also presents with defective healing, high fibrosis, inflammation and the development of very aggressive carcinomas (SCC), the cause of early mortality. RDEB is due to mutations in the COL7A1 gene that encodes type VII collagen (C7), a constitutive protein of anchor fibrils (AF) essential for deep dermo-epidermal adhesion, which is absent or greatly diminished in the most common forms. serious. Although permanent systemic replacement of C7 to correct the primary defect of the disease is curative, other strategies aimed at alleviating symptoms could have a clinically beneficial effect and improve the quality of life of patients. Among them are those aimed at mitigating progressive chronic manifestations related to scarring and fibrosis problems (pseudosyndactyly and cancer).

 

Within the framework of MULTITEREB, we have developed, at the preclinical level, innovative gene and pharmacological therapies for RDEB, thus contributing to the challenge of providing clinically relevant therapeutic solutions for this devastating rare disease. Our approach has been multimodal, aimed both at correcting the C7 deficit and the secondary complications responsible for the high morbidity of the disease:

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1) Through ex vivo gene editing (NHEJ repair) mediated by CRISPR / Cas9, we have efficiently corrected a highly prevalent mutation in the COL7A1 gene, obtaining a patent and the designation of an orphan drug that will be evaluated in the context of a clinical trial.

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2) We have also patented three DNA aptamers for the FPR2 receptor, which are highly stable molecules in the harsh environment of chronic ulcers and efficiently promote wound healing.

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3) Through molecular and functional screening, we have identified the relevance of the oxidative stress imbalance as a new event, which together with fibrosis and inflammation, could be a determining factor in tumor development in RDEB. Based on these results, we have patented the repositioning of two drugs for RDEB, raloxifene and N-acetylcysteine ​​(AC), since we have shown that they are capable of counteracting fibrosis and redox imbalance in cells of patients with the disease. Likewise, we have designed and characterized a new SCC model in RDEB, useful for the study of tumor initiation and progression processes, which also constitutes an ideal platform to evaluate new antitumor therapeutic strategies.

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Impact

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MULTITEREB has therefore contributed to face the socio-economic challenge represented by the cure of rare diseases, a health priority well recognized by THE SPANISH STRATEGY OF SCIENCE AND TECHNOLOGY AND OF INNOVATION within the Challenge in health, demographic change and well-being . MULTITEREB has addressed 3 of the 6 established thematic priorities (-omics, personalized medicine and evidence-based clinical and translational research).

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The results of MULTITEREB contribute:

a) a better understanding of the pathways and / or mechanisms in RDEB

b) reliable pre-clinical studies that facilitate the transfer of new therapies to the next level (clinical trials),

c) new directions to clinical research and, where appropriate, to medical practice, and

d) Greater attractiveness of Spain as a country that generates innovative therapeutic technologies.

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MULTITEREB has brought together experts in basic and translational biomedical research, dermatologists with vast experience and in clinical research with patients with EB; and has the support of patient associations that have guaranteed the translation / transfer of results. In the particular case of RDEB, the availability of a preventive / curative treatment developed within the framework of MULTITEREB could reduce the high cost it entails for families and the NHS.

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The scientific-technical results directly related to MULTITEREB are collected in 11 articles and 38 conference presentations. The use of these tools has also been extended to other forms of EB and even to other genodermatoses in collaboration with other national and international teams. MULTITEREB has contributed to consolidating other lines of research, with the clinical teams of the IIS-FJD and the La Paz hospital, of cell therapy for healing in RDEB and in ulcers associated with other highly prevalent pathologies, which frequently affect the population. older, another very vulnerable group. These results are collected in 5 other publications.