Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Recessive Dystrophic Epidermolysis Bullosa
• Intervention / Treatment: Drug: Gentamicin

• Study Type: Interventional
• Enrollment (Anticipated): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: David T Woodley, MD; Phone Number: 626-533-6028; Email: dwoodley@usc.edu
• Study Contact Backup: Name: Mei Chen, Ph.D; Phone Number: 323-865-0621; Email: chenm@usc.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • University of Southern California
      • Contact: Mei Chen, Ph.D; Phone Number: 323-865-0621; Email: chenm@usc.edu
      • Contact: David Woodley, MD; Phone Number: 323-865-0956; Email: dwoodley@usc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intravenous Gentamicin; 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; 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.; Other Names: Gentamicin Sulfate

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Southern California
• Investigators: Principal Investigator: David T. Woodley, MD, Professor, University of Southern California; Principal Investigator: Mei Chen, Ph.D, Professor, University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2018
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 2, 2018
• First Submitted That Met QC Criteria: January 2, 2018
• First Posted (Actual): January 8, 2018

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Nonsense Mutations
• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Collagen Diseases; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Gentamicins
• Other Study ID Numbers: HS-17-00995

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No