scholarly journals Immune reactivity to type VII collagen: implications for gene therapy of recessive dystrophic epidermolysis bullosa

Gene Therapy ◽  
2010 ◽  
Vol 17 (7) ◽  
pp. 930-937 ◽  
Author(s):  
V Pendaries ◽  
G Gasc ◽  
M Titeux ◽  
C Leroux ◽  
Z G Vitezica ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Epidermolysis Bullosa ◽  
Immune Reactivity ◽  
Dystrophic Epidermolysis Bullosa ◽  
Type Vii Collagen ◽  
Recessive Dystrophic Epidermolysis Bullosa

scholarly journals Development of Minicircle Vectors Encoding COL7A1 Gene with Human Promoters for Non-Viral Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa

2021 ◽  
Vol 22 (23) ◽  
pp. 12774
Author(s):  
Xianqing Wang ◽  
Fatma Alshehri ◽  
Darío Manzanares ◽  
Yinghao Li ◽  
Zhonglei He ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Gene Replacement ◽  
Epidermal Keratinocytes ◽  
Viral Gene ◽  
Cmv Promoter ◽  
Human Epidermal Keratinocytes ◽  
Dystrophic Epidermolysis Bullosa ◽  
Type Vii Collagen ◽  
Recessive Dystrophic Epidermolysis Bullosa ◽  
Col7a1 Gene

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare autosomal inherited skin disorder caused by mutations in the COL7A1 gene that encodes type VII collagen (C7). The development of an efficient gene replacement strategy for RDEB is mainly hindered by the lack of vectors able to encapsulate and transfect the large cDNA size of this gene. To address this problem, our group has opted to use polymeric-based non-viral delivery systems and minicircle DNA. With this approach, safety is improved by avoiding the usage of viruses, the absence of bacterial backbone, and the replacement of the control viral cytomegalovirus (CMV) promoter of the gene with human promoters. All the promoters showed impressive C7 expression in RDEB skin cells, with eukaryotic translation elongation factor 1 α (EF1α) promoter producing higher C7 expression levels than CMV following minicircle induction, and COL7A1 tissue-specific promoter (C7P) generating C7 levels similar to normal human epidermal keratinocytes. The improved system developed here has a high potential for use as a non-viral topical treatment to restore C7 in RDEB patients efficiently and safely, and to be adapted to other genetic conditions.

scholarly journals TGFβ-signaling in Squamous Cell Carcinoma Occurring in Recessive Dystrophic Epidermolysis Bullosa

2011 ◽  
Vol 34 (6) ◽  
pp. 339-353 ◽  
Author(s):  
Julia Knaup ◽  
Christina Gruber ◽  
Barbara Krammer ◽  
Verena Ziegler ◽  
Johann Bauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skin Cancer ◽  
Squamous Cell ◽  
Epidermolysis Bullosa ◽  
Chronic Wounds ◽  
Tgfβ Signaling ◽  
Dystrophic Epidermolysis Bullosa ◽  
Expression Levels ◽  
Type Vii Collagen ◽  
Recessive Dystrophic Epidermolysis Bullosa

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary skin disorder characterized by mechanical fragility of the skin, resulting in blistering and chronic wounds. The causative mutations lie in the COL7A1 gene. Patients suffering from RDEB have a high risk to develop aggressive, rapidly metastasizing squamous cell carcinomas (SCCs). Cutaneous RDEB SCCs develop preferentially in long-term skin wounds or cutaneous scars. Albeit being well differentiated, they show a more aggressive behavior than UV-induced SCCs. These findings suggest other contributing factors in SCC tumorigenesis in RDEB.Objective: To analyze factors contributing to RDEB tumorigenesis, we conducted a comprehensive gene expression study comparing a non-malignant RDEB (RDEB-CL) to a RDEB SCC cell line (SCCRDEB4) to achieve an overview on the changes of the gene expression levels in RDEB related skin cancer.Methods: We applied cDNA arrays comprising 9738 human expressed sequence tags (EST) with various functions. Selected results were verified by Real-time RT PCR.Results: Large-scale gene expression analysis revealed changes in the expression level of transforming growth factor β1 (TGFβ1) and several genes under the control of TGFβ for RDEB and SCCRDEB4 cell lines. Even untransformed RDEB keratinocytes show elevated levels of TGFβ1.Conclusion: Our findings demonstrate a prominent role of TGFβ-signaling in RDEB-related skin cancer. Once activated, TGFβ signaling either in response to wounding or in order to influence type VII collagen expression levels could facilitate cancer development and progression. Moreover, TGFβ signaling might also represent a potentially useful therapeutic target in this disease.

First Use of Allogeneic Stem Cells in the Treatment of Recessive Dystrophic Epidermolysis Bullosa: Demonstration of Biochemical and Clinical Improvement.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 660-660
Author(s):  
John E. Wagner ◽  
Akemi Ishida-Yamamoto ◽  
John A McGrath ◽  
Maria Hordinsky ◽  
Douglas R Keene ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epidermolysis Bullosa ◽  
Conflicts Of Interest ◽  
Dermal Matrix ◽  
Dystrophic Epidermolysis Bullosa ◽  
Type Vii Collagen ◽  
Male Sibling ◽  
Female Sibling ◽  
Recessive Dystrophic Epidermolysis Bullosa

Abstract Abstract 660 Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, often fatal mucocutaneous blistering skin disease caused by mutations in the type VII collagen (C7) gene, COL7A1. These pathogenic mutations result in severely diminished expression of C7, a collagen localized at the dermal-epidermal junction (DEJ), and absence of anchoring fibrils (AFs) which are C7 containing structures that tether the epidermal basement membrane to the dermal matrix. From birth on, children with RDEB develop painful erosions and blisters on mucosal membranes and skin often resulting in esophageal strictures, mutilating scarring, joint contractures, fusion of fingers and toes and, aggressive squamous cell carcinomas. After first demonstrating that a stem cell enriched fraction of bone marrow (BM) rescued a proportion of RDEB mice from lethality and resulted in a) expression of C7 in skin and mucosal membranes, b) formation of new AFs, and c) resistance to blistering, a ‘first-in-human' phase I-II clinical trial was initiated in October 2007. To date, 7 patients have been treated with stem cells from BM from an HLA matched sibling donor (n=6) or unrelated cord blood (CB) donor (n=1). Follow-up data are reported through August 18, 2009. Conditioning consisted of busulfan 0.8 mg/kg per dose every 6 hours on days–9 to–6, fludarabine 25 mg/m2/day on days–5 to–3, and cyclophosphamide 50 mg/kg/day on days–5 to–2. After infusion of stem cells on day 0, immunoprophylaxis consisted of cyclosporine and mycophenolate mofetil. Patient and graft characteristics are shown in Table 1. Of the 4 patients with adequate follow-up, a progressive increase in C7 deposition by immunofluorescence (IF) at the DEJ, AFs or AF-like structures by electron microscopy, and wound healing with marked reduction in blister formation were documented. Unexpectedly, all patients had substantial chimerism in the skin (11-93%) that persisted over time. In 2 patients with a sex mismatched donor, perivascular localization of the donor cells in the dermis could be discerned using probes to the centromere regions of chromosomes X and Y. In summary, this is the first demonstration that the infusion of BM can ameliorate the severe systemic mucocutaneous manifestations of RDEB and sets the stage for using marrow stem cells in the treatment of a broad spectrum of extracellular matrix disorders. PtDonor (cell dose: NC × 108/kg)Transplant Related ToxicitiesC7 AssessmentAnchoring Fibril AssessmentClinical OutcomeSurvival Days1 15 mo maleHLA 8/8 male sibling BM/CB (3.04; 0.66)NoneIncreased by IF↑ Rudimentary AFsImproved but no change in use of dressingsAlive day 6592 9 mo femaleHLA 8/8 male sibling BMCardiomyo-pathyNot evaluableNot evaluableNot evaluableDied day 03 5.9 maleHLA 5/6 female unrelated CB (0.55)Graft rejectionIncreased by IF and Western↑ Rudimentary AFsNot evaluableDied day 1834 6.3 yo maleHLA 8/8 female sibling BM (3.76)Transient Dialysis ARDSNo change by IF° but WesternNormal AFs observedMarked reduction in blisters and dressingsAlive day 2475 6.2 yo femaleHLA 8/8 male sibling BM (3.07)Transient DialysisIncreased by IF and Western↑ Rudimentary AFsMarked reduction in blisters and dressingsAlive day 1286 6.0 yo femaleHLA 8/8 female sibling BM (3.11)EpistaxispendingpendingEarly reduction in blisteringAlive day 567 14.5 yo femaleHLA 8/8 female sibling BMToo early to evaluatependingpendingToo early to evaluateAlive day -9 Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document