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MULTITEREB: Development and pre-clinical evaluation of advanced multimodal therapies for recessive dystrophic epidermolysis bullosa

Ongoing
Project leadM Del Río and MJ Escámez
Organisation CIEMAT - Centro de Investigaciones Energéticas Medioambientales y Tecnológicas
Partner organizations & collaboratorsUC3M- Universidad Carlos III de Madrid
Project budgetEUR 263.362,00
Start date / Duration01. Jan 2018 / 36 months
Funder(s) / Co-Funder(s) Others
Other funder(s)Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de investigación/ ERDF (European Regional Development Fund).
Research area Skin cancer & fibrosis, Molecular therapy, Symptom prevention & relief

Project details

Short lay summary

Recessive dystrophic epidermolysis bullosa (RDEB) is due to mutations in the gen coding for collagen VII (C7), which result in a drastic reduction or complete absence of C7. Therefore, people with RDEB have skin and mucosa fragility, blisters, painful chronic wounds and fibrosis related to the development of deformities and aggressive carcinomas. MULTITEREB investigates strategies for a definitive (gene editing) and/or for the prevention and relief of fibrosis and chronic wounds (drug repositioning and aptamers). Gene editing consist in using sophisticated molecular tools for cutting and pasting of the mutated region of the RDEB-causative gene to restore permanently the expression of C7 and its function (at local level). The use of drugs available in the pharmacies for the treatment of other diseases (repositioned drugs) whose molecular action influence the TGF-beta pathway could prevent or ameliorate fibrosis. Aptamers are small therapeutics molecules that may promote wound healing, by the recognition of specific receptors present on the skin and other tissues affected in RDEB patients (cornea, nasopharyngeal tract and esophagus).

Scientific summary

Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by extreme fragility of the skin and mucous membranes, aberrant scarring, elevated fibrosis and development of very aggressive carcinomas that cause early lethality. RDEB is due to mutations in the COL7A1 gene encoding type VII (C7) collagen, a constitutive protein of the anchor fibrils that are fundamental for deep dermo-epidermal adhesion, absent or greatly diminished in the generalized severe variant (RDEB sev-gen). Although C7 replacement required for the correction of the primary defect of the disease is presumed to be curative, recent evidence suggests that other therapeutic strategies designed to mitigate progressive chronic manifestations related to scarring and fibrosis problems (e.g. pseudosyndactily and cancer) may have a highly beneficial effect on the quality of life of patients. With this premise and an supported by preliminary results, we propose the development of innovative genetic and pharmacological therapies aimed at both the correction of the C7 deficit and the secondary defects responsible for the high morbidity of the EBDR. In particular, we will study the efficacy of: 1) new ex vivo gene editing strategies based on NHEJ mediated by TALEN and CRISPR/Cas9 nuclease repair to correct a recurrent mutation in the COL7A1 gene; 2) pharmacological approaches based on the inhibition of TGFβ signaling that allow stromal normalization to attenuate/inhibit tumor development in RDEB and 3) a therapeutic strategy to promote healing of chronic wounds based on the application of functionalized DNA aptamers as ligands for receptors of the FPR2 family. These protocols will be tested in reliable models of the disease with a high probability of predicting a clinical response.

Strategic relevance

The success of these strategies to ameliorate skin fragility, fibrosis and/or wound healing may be critical to alleviate pain, itching and, to reduce the development of skin cancer. The biosafety of the strategies make them translatable to the clinics: 1) Gene editing does not use viral vectors; 2) Repositioned drugs are already widely used in the clinics and, 3) Aptamers (stability on the hostile wound environment, no immunogenicity and not toxicity) have already been approved by Health authorities to be used to treat age-related macular degeneration. If any of the strategies were efficient, orphan drug designation would be requested. In the case of gene editing the next step would be the implementation of a clinical trial. In term of cost, repositioned drugs (already marketed) and aptamers (low cost production), translation to the clinics must be easy and fast.


Keywords

Dystrophic Epidermolysis bullosa
Rare diseases
gene therapy
pharmacology
drug repositioning
aptamers
genodermatosis
fibrosis
chronic wounds
Cancer
Del Río
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