Gene Therapy for Epidermolysis Bullosa

Marinkovich, M. Peter; Tang, Jean Y.

doi:10.1016/j.jid.2018.11.036

Cited by 62 publications

(47 citation statements)

References 76 publications

(77 reference statements)

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“…Evaluation of C7 molecular correction by biopsy can be challenging, and not all biopsies of treated sites were positive for the NC2 domain of C7 and/or AFs. Biopsy results could be affected by site-selection bias or driven by heterogeneous expression of C7 due to infiltration of noncorrected native epidermal stem cells that persist despite surgical preparation of the wound bed before treatment (15). Also, while many previous RDEB studies examined only the C7 NC1 domain, we focused on the NC2 domain, which is more indicative of…”

Section: Discussionmentioning

confidence: 99%

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa

et al. 2019

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Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, life-threatening bullous genodermatosis (1, 2). Genetic mutations in the COL7A1 gene lead to lack of functional type VII collagen (C7), a large triple-helical protein found beneath the lamina densa (2-4). C7 contains 2 noncollagenous domains (NC1 and NC2) and a central collagenous domain, forming anchoring fibrils (AFs) that are critical to dermal-epidermal basement cohesion (2, 4). Mutations in COL7A1 lead to disruptions in keratinocyte adhesion, reducing mucocu-BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy. METHODS. Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm 2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years. RESULTS. No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019). CONCLUSION. C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patientreported outcomes. TRIAL REGISTRATION. Clinicaltrials.gov identifier: NCT01263379.

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Section: Discussionmentioning

confidence: 99%

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa

et al. 2019

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“…Many laboratories, in both academia and the pharmaceutical sector, have focused on gene-replacement approaches, particularly delivery of COL7A1 to the skin of patients with RDEB (Table 1). For details on methods, hurdles and risks, we refer to recent review articles [27,28]. Some studies have tested the efficacy of topical application of an expression vector harboring full-length COL7A1 complementary DNA (cDNA), which would then allow expression of the proα1(VII) polypeptides in the skin, followed by their incorporation into trimeric type VII collagen molecules and supramolecular assembly into functional anchoring fibrils.…”

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%

“…The spectrum comprises of corrective and symptom-relieving therapies, including innovative therapeutic components from the bench, repurposed drugs approved for other (more common) diseases like cancers or immune disorders, as well as strategies for gene-, protein-, cell-based and small molecule therapies. [7][8][9]…”

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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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Gene Therapy for Epidermolysis Bullosa

Cited by 62 publications

References 76 publications

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

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

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