Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Study Overview
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Brief Summary
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Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, devastating, inherited skin disease caused by mutations in the COL7A1 gene that encodes for type VII collagen (C7), the major component of anchoring fibrils (AFs), structures that mediate epidermal-dermal adherence. Thirty percent of RDEB patients have nonsense mutations. The investigators recently demonstrated in 5 such patients that intradermal and topical gentamicin induced read-through of their nonsense mutations and created robust and sustained new C7 and AFs at the dermal-epidermal junction (DEJ) of their skin and also stimulated wound closure and reduced new blister formation. No untoward side effects occurred. Herein, the investigators propose evaluating the safety and efficacy of intravenous gentamicin in these patients. In theory, this intravenous administration has the possibility of treating simultaneously all of the patients' skin wounds. The milestones will be increased C7 and AFs in the patients' DEJ, improved EB Disease Activity Scores, and absence of gentamicin side effects.

Official Title
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Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment

Conditions
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Recessive Dystrophic Epidermolysis Bullosa

Intervention / Treatment
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* Drug: Gentamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged 7 and up can participate in the 14 day IV gentamicin trial. Male or female, aged 18 and up can participate in the 3 month IV gentamicin trial. Been diagnosed with recessive dystrophic epidermolysis bullosa (RDEB) and with a nonsense mutation in the COL7A1 gene. Immunofluorescence evaluation of skin biopsies reveals absence or decreased intensity of C7 expression at their DEJ (dermal epidermal junction) compared with normal human skin biopsies. Cultured fibroblasts from patient skin synthesize and secrete full-length, 290kDa C7 alpha chains in the presence of supplemented gentamicin (400 μg/ml in culture). Ability to sit or lie down for over 30 minutes for IV infusions. For those in the 3 month trial, to be willing to continue treatment at home under the supervision of licensed and trained infusion nurses. Exclusion Criteria: Recent exposure to gentamicin within the past 6 weeks. Pre-existing known auditory impairment. Pre-existing known renal impairment. Pre-existing known allergies to aminoglycosides or sulfate compounds. Pregnancy or lactation Current use of medications with known ototoxicity or nephrotoxicity. Current enrollment in another experimental clinical trial involving systemic treatment with C7 or C7 producing products for the treatment of RDEB.

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Gentamicin<br>Intravenous gentamicin (7.5 mgs/kg) daily for for either 14 days and then stopped or twice weekly for three months and then stopped. | Drug: Gentamicin<br>* Short-term intravenous gentamicin therapy should have the advantage of treating all of the patient's multiple skin wounds simultaneously. Six patients (three adults and 3 children) will receive intravenous gentamicin (7.5 mgs/kg) daily for 14 days and then stopped. Three adult patients will receive intravenous gentamicin (7.5mg/kg) biweekly for three months and then stopped.<br>* Other names: Gentamicin Sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full-length type VII collagen expression | Increased expression of full-length type VII collagen as assessed by immunofluorescence | 6 months | 
| Generation of anchoring fibrils | Generation of new anchoring fibrils as assessed by immuno-electron microscopy | 6 months | 
| Absence of gentamicin side effects | Absence of gentamicin side effects, especially the detection of any ototoxicity or nephrotoxicity | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improved Disease Activity scores | Improved epidermolysis bullosa Disease Activity scores | 6 months | 
| Improved Quality of Life score | Improved Quality of Life score | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonsense Mutations