Clinical trial NCT03392909: Intravenous Gentamicin Therapy for Recessive Dystrophic Epidermolysis Bullosa (RDEB)
Official title: Restoration of Full-Length Type VII Collagen in RDEB Patients With Nonsense Mutations After Intravenous Gentamicin Treatment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Recessive Dystrophic Epidermolysis Bullosa
Keywords: Nonsense Mutations
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2018-01-08
Enrollment: 9
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Full-length type VII collagen expression
timeFrame: 6 months
measure: Generation of anchoring fibrils
timeFrame: 6 months
measure: Absence of gentamicin side effects
timeFrame: 6 months
Secondary outcomes:
measure: Improved Disease Activity scores
timeFrame: 6 months
measure: Improved Quality of Life score
timeFrame: 6 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
Study officials:
affiliation: Professor, University of Southern California
name: David T. Woodley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Professor, University of Southern California
name: Mei Chen, Ph.D
role: PRINCIPAL_INVESTIGATOR
References: