EBGene trial: patient preselection outcomes for the European GENEGRAFT
            <i>ex vivo</i>
            phase I/II gene therapy trial for recessive dystrophic epidermolysis bullosa

Gaucher, Sonia; Lwin, Su M.; Titeux, Matthias; Abdul‐Wahab, Alya; Pironon, N.; Izmiryan, Araksya; Miskinyte, S.; Ganier, Clarisse; Duchatelet, Sabine; Mellerio, Jemima E.; Bourrat, E.; McGrath, John A.; Hovnanian, Alain

doi:10.1111/bjd.18559

Cited by 20 publications

(14 citation statements)

References 8 publications

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“…Gene therapies aim at replacing or correcting disease-causing gene mutations in ex vivo patient cells, including induced pluripotent stem cells (iPSCs) [97], fibroblasts [98,99], and keratinocytes with high growth potential, termed holoclones. Different strategies ranging from retroviral-mediated gene transfer to genome editing (e.g., TALENs and CRISP/CAS9 systems) [100,101,102,103,104,105] can be used for gene correction in patient cells.…”

Section: Dystrophic Ebmentioning

confidence: 99%

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

Condorelli

Dellambra

Logli

et al. 2019

IJMS

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Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.

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Section: Dystrophic Ebmentioning

confidence: 99%

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

Condorelli

Dellambra

Logli

et al. 2019

IJMS

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“…All these three combinations of cells in skin-equivalent explant culture ex vivo expressed type VII collagen, but only the grafts in which both keratinocytes and fibroblasts were gene corrected showed assembly of functional anchoring fibrils. In keeping with these data, there is an ongoing effort to develop skin grafts (GENEGRAFT) that combine keratinocytes and fibroblasts in which both cell types have been corrected with a self-inactivating viral vector expressing type VII collagen [33].…”

Section: Gene-replacement Therapiesmentioning

confidence: 99%

“…Epidermal grafts have been shown to be highly successful in correcting the underlying defect in patients with intermediate or localized JEB with defects in one of the laminin 332 genes, LAMB3 [33][34][35]. The difference with these studies and those published on grafting in patients with RDEB is that the grafts for patients with JEB were made of a holoclone stem cell population, thus ensuring the longevity of the cells after transplantation.…”

Section: Gene-replacement Therapiesmentioning

confidence: 99%

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

2020

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Epidermolysis bullosa (EB) is a group of rare genetic disorders for which significant progress has been achieved in the development of molecular therapies in the last few decades. Such therapies require knowledge of mutant genes and specific mutations, some of them being allele specific. A relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs, mainly in recessive dystrophic EB. It is expected that some new drugs may emerge in the near future and that combinations of different approaches may result in improved treatment outcomes for individuals with EB. Key PointsRemarkable progress has been made in understanding the molecular genetics and underlying pathomechanisms of epidermolysis bullosa (EB) forming the platform for development of treatments.Gene-replacement approaches, particularly delivery of COL7A1 to the skin of patients with severe dystrophic EB, type VII collagen replacement, skipping of exons and read-through of premature termination codons are currently in clinical trials.Preclinical research explores the applicability of new strategies in regenerative medicine (e.g., induced pluripotent stem cells) and genome editing (e.g., CRISPR/ Cas9).Particular effort is focused on severe dystrophic EB, characterized by extensive scarring and aggressive squamous cell carcinomas. Small molecules repurposed to reduce fibrosis, and the multikinase inhibitor rigosertib-for the treatment of recessive dystrophic EB squamous cell carcinomas-are being tested in clinical trials.

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“…This therapeutic modality has entered clinical development, employing transposons, retroviral or lentiviral vectors (Table 1). [7,8,[93][94][95] Ex vivo gene delivery approaches have proven to give rise to long-lasting, biomechanically sound grafts in junctional EB patients with LAMB3 mutations. [32,[96][97][98] However, technological issues relating to vector safety (ie risk of insertional mutagenesis), optimal delivery (especially of large genes like COL7A1), identification and targeting of holoclone stem cells (ie long-lived epidermal stem cells with high colony-forming efficiency [99] ), as well as transfection/ transduction efficiency to reach stable and controlled integration and activity of the transgene, hitherto limit the availability and long-term effects of such treatments.…”

Section: Tre Atment Op Ti On S With Cur Ative P Otentialmentioning

confidence: 99%

“…This therapeutic modality has entered clinical development, employing transposons, retroviral or lentiviral vectors (Table 1). [ 7,8,93–95 …”

Section: Treatment Options With Curative Potentialmentioning

confidence: 99%

Translational perspectives to treat Epidermolysis bullosa—Where do we stand?

Prodinger

Bauer

Laimer

2020

Experimental Dermatology

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Epidermolysis bullosa (EB) comprises a group of rare, genetically determined skin fragility disorders characterized by (muco-) cutaneous blistering following mild mechanical trauma. The most recent classification guidelines published in February 2020 define EB as the prototypic genetic disorder of skin fragility. Other skin fragility disorders, including peeling skin disorders, erosive disorders, hyperkeratotic disorders and connective tissue disorders with skin fragility, are now classified as a separate category, that is so-called

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EBGene trial: patient preselection outcomes for the European GENEGRAFT ex vivo phase I/II gene therapy trial for recessive dystrophic epidermolysis bullosa

Cited by 20 publications

References 8 publications

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

Translational perspectives to treat Epidermolysis bullosa—Where do we stand?

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