Nuria Illera

Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis caused by loss-of-function mutations in the COL7A1 gene, producing a complex and heterogeneous phenotype. Clinical manifestations include skin fragility, local and systemic inflammation, impaired wound healing, dysbiosis, pain, and pruritus, increasing the risk of skin cancer. This work aimed to develop an actionable model of RDEB’s molecular mechanisms to identify and prioritize therapeutic targets for drug repurposing. Transcriptomic data of skin biopsies from pediatric RDEB patients and unaffected individuals were used to build the mechanistic map of the disease. This model, combined with machine learning, made it possible to infer actionable targets from the map circuits and identify candidate drugs capable of reversing the transcriptomic alterations. The resulting map is defined by 13 altered signaling circuits and 10 effector proteins which were linked to disease hallmarks including inflammation, fibrosis, and tumor progression. Analysis of the map identified 66 actionable targets with 74 drug candidates. Among them, overrepresentation analysis showed enrichment of phosphodiesterases and antineoplastic and immunomodulating agents. Finally, 16 drugs were prioritized for their potential to revert circuit alterations without potentiating unintended effects, with bendroflumethiazide and ibutilide showing the highest impact. This mechanistic model delivers the first functional disease map of RDEB and reveals promising therapeutic candidates targeted by approved drugs.

Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering genodermatosis due to biallelic loss-of-function variants in the type VII collagen (C7) gene (COL7A1). We report the impact of inflammation/autoimmunity on the gut (and other organs) in the nine children with RDEB recruited to an early-phase clinical trial of systemic cell therapy (NCT04153630). This pilot study provides evidence that autoimmunity may play an important role in sustaining chronic inflammation and the coexistence of coeliac disease, which, in turn, could exacerbate anaemia/malnutrition and progression in RDEB. Testing this hypothesis in a larger cohort including children and adults with RDEB and other epidermolysis bullosa (EB) subtypes is warranted so that targeted interventions may improve outcomes.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable rare skin fragility disorder characterized by deficient dermo-epidermal adhesio | POSTER

Recessive dystrophic epidermolysis bullosa(RDEB),due to mutations in COL7A1 encoding collagen 7,is a rare incurable skin fragility disease accomp | POSTER

Epidermolysis Bullosa is a clinically and genetically heterogeneous rare blistering skin disorder. The most severe variant, Recessive Dystrophic | POSTER

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelicCOL7A1gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 10⁶cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6–9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.

Psoriasis is a complex inflammatory skin disease that presents a wide variety of clinical manifestations. Human β defensin‐2 (hBD‐2) is highly up‐regulated in psoriatic lesions and has been defined as a biomarker for disease activity. We explored the potential benefits of targeting hBD‐2 by topical application of DEFB4‐siRNA‐containing SECosomes in a bioengineered skin‐humanized mouse model for psoriasis. A significant improvement in the psoriatic phenotype was observed by histological examination, with a normalization of the skin architecture and a reduction in the number and size of blood vessels in the dermal compartment. Treatment leads to the recovery of transglutaminase activity, filaggrin expression and stratum corneum appearance to the levels similar to those found in normal regenerated human skin. The availability of a reliable skin‐humanized mouse model for psoriasis in conjunction with the use of the SECosome technology may provide a valuable preclinical tool for identifying potential therapeutic targets for this disease.