Characterization of novel fibrosis modulators in recessive dystrophic EB (León 1)

Short lay summary

In RDEB, the high stiffness of the skin's connective tissue, known as fibrosis, represents a serious complication of the disease that leads to scarring, mitten-like deformities, and cancer development. Decreasing the fibrotic process can help a lot to improve the patient's quality of life. This group identified in fibroblasts from a RDEB patient with an unexpected mild phenotype a molecule called PRELP, an extracellular matrix proteoglycan that, like Decorin, another member of the proteoglycan family, may have antifibrotic properties. In this project the team will study, on the one hand, whether the fibroblasts of patients with mild RDEB may contain a specific subpopulation that is really responsible for antifibrotic activity and, if so, they will try to characterize them in detail. On the other hand, the team lead by Prof Carlos León and Prof Fernando Larcher will evaluate whether PRELP can prevent or counteract some of the fibrotic manifestations in a mouse model of RDEB. Successful results may lead to the addition of PRELP as a valuable therapeutic molecule for RDEB.

Scientific summary

In patients with RDEB, persistent inflammation, fibrosis, and squamous cell carcinoma (SCC) represent serious complications of the disease derived from the aberrant healing of chronic wounds, associated in some way with the primary deficiency of type VII collagen (C7). Early restoration of C7 by any of the various pharmacological, cell, and gene therapy approaches could prevent the development or progression of fibrotic, inflammatory, and oncogenic events. Even so, there is an urgent need to attenuate or prevent these serious manifestations by also addressing their mediators such as TGF-β signaling which plays a key role in the establishment and maintenance of the fibrotic process. In addition to seeking therapeutic solutions involving cell and gene therapy for RDEB, the laboratory is making efforts to understand the fibrotic process to be able to provide evidence-based relief therapies.

Unusual clinical of RDEB siblings with markedly discordant clinical presentation (i.e., mild versus severe), despite sharing an identical COL7A1 genotype, provide unique opportunities to better understand the pathogenesis of the disease and to recognize possible compensatory mechanisms that modulate the clinical condition. The research team presents strong preliminary evidence, based on the study of the behavior of fibroblasts from two RDEB siblings with remarkable phenotypic variation, about the role of the proteoglycan Prolargin (PRELP) as a plausible modulator of the severity of RDEB and they postulate it as a symptoms relief candidate to treat fibrotic/oncogenic complications.

In view of these preliminary results the team proposes two main specific objectives or Work Packages (WP): WP1 involves further phenotypic characterization of fibroblasts from mild and severe RDEB siblings. WP2 involves in vitro and in vivo functional studies of PRELP with respect to its putative pro-adhesive, antifibrotic, and antitumor properties.

Strategic relevance

The restoration of cutaneous homeostasis as a consequence of collagen type VII (C7) deficiency in patients with RDEB is of paramount importance. Therefore, the replacement of C7 remains the main therapeutic objective, but counteracting fibrosis is also of great relevance. The role of functional disruption of TGF beta as a major player in the establishment and progression of fibrosis has been well characterized. However, despite various efforts, researchers in the field have not yet come up with an effective and practical way to inhibit/mitigate its harmful effects. Therefore, the identification of molecules such as PRELP with the ability to restore cutaneous homeostasis remains essential to increase the therapeutic arsenal. Once identified, it is mandatory and strategically relevant to test these molecules in suitable models of disease, as proposed in this project.