Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients
David T. Woodley, … , Douglas Keene, Mei Chen
David T. Woodley, … , Douglas Keene, Mei Chen
Published July 10, 2017
Citation Information: J Clin Invest. 2017;127(8):3028-3038. https://doi.org/10.1172/JCI92707.
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Clinical Research and Public Health Dermatology

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

Abstract

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. FUNDING. Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH, and VA Merit Award.

Authors

David T. Woodley, Jon Cogan, Yingping Hou, Chao Lyu, M. Peter Marinkovich, Douglas Keene, Mei Chen

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Figure 3

Topical or intradermal gentamicin treatment generated new AFs in RDEB patients.

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Topical or intradermal gentamicin treatment generated new AFs in RDEB pa...
Skin sections taken from patients 3 and 4 at 1 month and 3 months after treatment, as indicated, were subjected to IEM by labeling en bloc with a murine monoclonal antibody, mAb 185, to type VII collagen, followed by anti-mouse IgG–conjugated immunogold particles (black dots). The photomicrographs consist of low magnification images shown in A with black boxes highlighting the regions shown in the high magnification images (B). Note that in the placebo-treated test sites, there was no labeling of the DEJ and there were no visible AFs in either patient. In contrast, skin biopsy samples from both topical and intradermally injected gentamicin test sites exhibited intense gold labeling of the lamina densa and many well-labeled AFs (arrows). Scale bars: 250 nm (A); 100 nm (B).