Epidermolysis Bullosa Simplex: A Clinical Overview

Lin, Andrew N.; Carter, D. Martin

doi:10.1007/978-1-4612-2914-8_7

Cited by 8 publications

(8 citation statements)

References 98 publications

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“…Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, inherited skin disease characterized by skin fragility, blisters, erosions, and scarring (1). RDEB is caused by mutations in the COL7A1 gene that encodes type VII collagen, the major component of anchoring fibrils (AFs) that tether together the 2 main layers of skin, the epidermis and dermis (2,3).…”

Section: Introductionmentioning

confidence: 99%

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Woodley¹,

Cogan²,

Hou³

et al. 2017

Journal of Clinical Investigation

100

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BACKGROUND.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. METHODS.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. RESULTS.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.CONCLUSION. 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. TRIAL REGISTRATION. ClinicalTrials.gov NCT02698735.

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Section: Introductionmentioning

confidence: 99%

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Woodley¹,

Cogan²,

Hou³

et al. 2017

Journal of Clinical Investigation

100

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“…On the basis of the level of cleavage of the skin leading to blister formation, EB has been divided into three broad categories (Fine et al 1991;Lin and Carter 1992). The simplex forms of EB are those in which blisters develop intraepidermally at the level of the basal keratinocytes, above the basement membrane.…”

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confidence: 99%

“…Finally, all forms of both dominantly and recessively inherited dys trophic EB result from mutations in the type VII collagen gene (Uitto and Christiano 1992;Christiano and Uitto I996a,b). Although the molecular basis of many of the classic forms of EB are now well understood, a small group of patients exhibit the formation of blisters in the region of the hemidesmosome, the ultrastructural clas sification and clinical severity of which have been re ferred to as "pseudojunctional" (Fine et al 1991;Lin and Carter 1992).…”

mentioning

confidence: 99%

Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.

McLean¹,

Pulkkinen²,

Smith³

et al. 1996

Genes Dev.

286

209

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Plectin is a widely expressed high molecular weight protein that is involved in cytoskeleton-membrane attachment in epithelial cells, muscle, and other tissues. The human autosomal recessive disorder epidermolysis bullosa with muscular dystrophy (MD-EBS) shows epidermal blister formation at the level of the hemidesmosome and is associated with a myopathy of unknown etiology. Here, plectin was found to be absent in skin and cultured keratinocytes from an MD-EBS patient by immunofluorescence and immunoprecipitation, suggesting that plectin is a candidate gene/protein system for MD-EBS mutation. The 14800-bp human plectin cDNA was cloned and sequenced. The predicted 518-kD polypeptide has homology to the actin-binding domain of the dystrophin family at the amino terminus, a central rod domain, and homology to the intermediate filament-associated protein desmoplakin at the carboxyl terminus. The corresponding human gene (PLECl), consisting of 33 exons spanning >26 kb of genomic DNA was cloned, sequenced, and mapped to chromosomal band 8q24. Homozygosity by descent was observed in the consanguineous MD-EBS family with intragenic plectin polymorphisms. Direct sequencing of PCR-amplified plectin cDNA from the patient's keratinocytes revealed a homozygous 8-bp deletion in exon 32 causing a frameshift and a premature termination codon 42 bp downstream. The clinically unaffected parents of the proband were found to be heterozygous carriers of the mutation. These results establish the molecular basis of MD-EBS in this family and clearly demonstrate the important structural role for plectin in cytoskeleton-membrane adherence in both skin and muscle.

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“…We had previously developed a cell based approach for treating acute cutaneous injuries and blistering disorders classified as epidermolysis bullosa (EB; Lin and Carter, 1992). The acute injury considered for therapeutic intervention is the result of exposure to sulfur mustard (bis-(2-chloroethyl) sulfide; HD), a chemical warfare agent that alkylates DNA, RNA and proteins.…”

Section: Introductionmentioning

confidence: 99%

Keratinocyte Spray Technology for the Improved Healing of Cutaneous Sulfur Mustard Injuries

Simon¹,

McClain²,

Zimmerman³

2009

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Epidermolysis Bullosa Simplex: A Clinical Overview

Cited by 8 publications

References 98 publications

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.

Keratinocyte Spray Technology for the Improved Healing of Cutaneous Sulfur Mustard Injuries

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