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This genetic blistering disease is the result of mutations in COL7A1 , which encodes type VII collagen. Topical HSV-1 gene therapy delivering COL7A1 resulted in greater wound healing at 6 months than placebo.

Recessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1 , the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain–severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB. Preclinical data and results from a phase 1 and 2 trial demonstrate preliminary safety and efficacy of topical gene therapy for recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the COL7A1 gene encoding type VII collagen. Individuals with RDEB have fragile skin and most develop large, chronic wounds. The aim of the VIITAL study was to evaluate the efficacy and safety of a one-time surgical application of prademagene zamikeracel in wound healing. This randomised, open-label, intrapatient-controlled, phase 3 trial was conducted at two institutions in the USA. Eligible patients were aged 6 years or older, had a confirmed clinical and genetic diagnosis of RDEB, at least two chronic wounds (>20 cm2), had no evidence of an immune response to type VII collagen, and expressed the amino-terminal NC1 fragment of type VII collagen. Large, chronic wounds on the participants were matched in pairs by size, chronicity, and anatomical region and computer randomised (1:1) to treatment (prademagene zamikeracel) or control (standard of care). There was no masking. Prademagene zamikeracel is an autologous COL7A1 gene-modified cellular sheet that is sutured onto to a large, chronic RDEB wound. A maximum of six wounds could be treated with prademagene zamikeracel per patient. The coprimary endpoints were the proportion of wounds with at least 50% healing and pain reduction from baseline at week 24 in the intention-to-treat population of all patients and their randomised wounds. The safety analysis population included all patients and evaluated wounds, randomised and non-randomised. This completed trial was registered with ClinicalTrials.gov (NCT04227106). Between Jan 1, 2020, and March 31, 2022, 15 patients were screened and 11 were enrolled (43 randomised wound pairs). Four (36%) of 11 participants were male and seven (64%) of 11 participants were female, with a median age of 21 years (IQR 17–30). 86 wounds were matched and randomised: 43 (50%) to prademagene zamikeracel and 43 (50%) to control. At week 24, 35 (81%) of 43 treated wounds were at least 50% healed from baseline for prademagene zamikeracel compared with seven (16%) of 43 control wounds (mean difference 67% [95% CI 50 to 89]; p<0·0001). The mean change from baseline to week 24 in wound pain was –3·07 with prademagene zamikeracel and –0·90 in controls (mean pairwise difference –2·23 [–3·45 to –0·66]; p=0·0002). No serious treatment-related adverse events were observed. Prademagene zamikeracel improved wound healing and pain versus control and was well tolerated, supporting its potential to reduce wound burden in patients with large, chronic RDEB wounds. Abeona Therapeutics.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions. Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti-type VII collagen autoantibodies in patients' blood or skin. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations. ClinicalTrials.gov NCT02698735. Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH, and VA Merit Award.

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. Methods Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm 2 ) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. Results Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4–8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing ( p  < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. Conclusions Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. Trial registration ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379

The use of marrow stem cells to treat seven children with severe epidermolysis bullosa caused by loss-of-function mutations in COL7A, the gene encoding type VII collagen (C7), was examined. The investigators observed increases in C7 deposition, the presence of donor cells in the skin, and an amelioration of symptoms. Loss of skin integrity that leads to trauma-induced blisters and erosions is a defining feature of epidermolysis bullosa, a heterogeneous group of more than 20 inherited blistering diseases with highly variable clinical severity. 1 One of the most severe forms is recessive dystrophic epidermolysis bullosa, caused by loss-of-function mutations in the collagen type VII (C7) gene ( COL7A1 ). 2 – 6 These mutations result in severely diminished expression of C7, a collagen localized at the dermal–epidermal junction. C7 is the major component of the anchoring fibrils that tether the epidermal basement membrane to the dermal matrix. In the absence of normal C7 . . .

Base editing introduces precise single-nucleotide edits in genomic DNA and has the potential to treat genetic diseases such as the blistering skin disease recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by mutations in the COL7A1 gene and type VII collagen (C7) deficiency. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Here, we use ABE8e, a recently evolved ABE, to correct primary RDEB patient fibroblasts harboring the recurrent RDEB nonsense mutation c.5047 C > T (p.Arg1683Ter) in exon 54 of COL7A1 and use a next generation sequencing workflow to interrogate post-treatment outcomes. Electroporation of ABE8e mRNA into a bulk population of RDEB patient fibroblasts resulted in remarkably efficient (94.6%) correction of the pathogenic allele, restoring COL7A1 mRNA and expression of C7 protein in western blots and in 3D skin constructs. Off-target DNA analysis did not detect off-target editing in treated patient-derived fibroblasts and there was no detectable increase in A-to-I changes in the RNA. Taken together, we have established a highly efficient pipeline for gene correction in primary fibroblasts with a favorable safety profile. This work lays a foundation for developing therapies for RDEB patients using ex vivo or in vivo base editing strategies.

Epidermolysis Bullosa (EB) is a rare genetic disorder that results in fragile skin and blistering and may lead to mucous membrane involvement. The disease manifests in several subtypes, among which the most serious conditions are dystrophic and junctional EB. This study intends to highlight the recurrent and novel genetic abnormalities that cause EB in the Western region of Saudi Arabia. Twelve Middle Eastern Arab families affected by Epidermolysis Bullosa (EB) were recruited from dermatology clinic from King Abdullah Medical Complex in Jeddah. Detailed clinical phenotyping was conducted for each patient to document EB-associated symptoms and to accurately determine the disease subtypes. Whole Exome Sequencing (WES) was performed to identify genetic variants associated with EB, and the resulting variants were classified by the guidelines of the American College of Medical Genetics and Genomics (ACMG). Additionally, multiple bioinformatics tools were employed to evaluate the pathogenicity of the detected variants. Variant segregation with disease phenotype was confirmed within the families using Sanger sequencing. We identified 11 genetic variants, including three novel variants, in the COL7A1 (NM_000094.4), COL17A1 (NM_000494.4), and LAMB3 (NM_000228.3) genes across 12 EB families. The COL7A1 variants included frameshift variants (c.5924_5927del and c.6268_6269del), nonsense variants (c.1633C > T, c.1837C > T, c.2005C > T, and c.5888G > A), missense variants (c.4448G > A and c.8245G > A), and splice-site variants (c.6751-1G > A and c.8305-1G > A). Additionally, a splice-site variant was identified in COL17A1 (NM_000494.4; c.1394G > A) and another in LAMB3 (NM_000228.3; c.1977-1G > A). Bioinformatics analysis predicted these variants to be likely pathogenic because they disrupt collagen VII, XVII, and laminin 332, proteins essential for skin stability. Frameshift and nonsense variants introduce premature stop codons, leading to truncated or degraded transcripts. Splice-site variants likely cause aberrant splicing, disrupting the reading frame and impairing protein function. WES is an effective first-line diagnostic tool for identifying EB-associated variants. This study reveals locus and allelic heterogeneity in EB cases from Saudi Arabia. The findings underscore the importance of early genetic screening for improving genetic counseling in high-consanguinity populations and emphasize the need for large-scale genetic studies in the country.

The interaction between cells and extracellular matrix (ECM) has been recognized in the mechanism of fibrotic diseases. Collagen type VII (collagen VII) is an ECM component that plays an important role in cell-ECM interaction, particularly in cell anchoring and maintenance of ECM integrity. Pleural mesothelial cells (PMCs) drive inflammatory reactions and ECM production in pleura. However, the role of collagen VII and PMCs in pleural fibrosis was poorly understood. In this study, collagen VII protein was found to be increased in pleura of patients with tuberculous pleural fibrosis. Investigation of cellular and animal models revealed that collagen VII began to increase at an early stage in the pleural fibrotic process. Increase of collagen VII occurred ahead of collagen I and α-SMA in PMCs and pleura of animal models. Inhibition of collagen VII by mesothelial cell-specific deletion of collagen VII gene (Wt1-Cre+ Col7a1fl/fl) attenuated mouse experimental pleural fibrosis. Finally, it was found that excessive collagen VII changed collagen conformation, which resulted in elevation of ECM stiffness. Elevation of ECM stiffness activated integrin/PI3K-AKT/JUN signaling and promoted more ECM deposition, as well as mediated pleural fibrosis. In conclusion, excessive collagen VII mediated pleural fibrosis via increasing ECM stiffness.

Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by a functional deficit of type VII collagen protein due to gene defects in the type VII collagen gene (COL7A1). Gene augmentation therapies are promising, but run the risk of insertional mutagenesis. To abrogate this risk, we explored the possibility of using engineered transcription activator-like effector nucleases (TALEN) for precise genome editing. We report the ability of TALEN to induce site-specific double-stranded DNA breaks (DSBs) leading to homology-directed repair (HDR) from an exogenous donor template. This process resulted in COL7A1 gene mutation correction in primary fibroblasts that were subsequently reprogrammed into inducible pluripotent stem cells and showed normal protein expression and deposition in a teratoma-based skin model in vivo. Deep sequencing-based genome-wide screening established a safety profile showing on-target activity and three off-target (OT) loci that, importantly, were at least 10 kb from a coding sequence. This study provides proof-of-concept for TALEN-mediated in situ correction of an endogenous patient-specific gene mutation and used an unbiased screen for comprehensive TALEN target mapping that will cooperatively facilitate translational application.