Clinical trial NCT03526159: Gentamicin for Junctional Epidermolysis Bullosa
Official title: A Pilot Study of the Restoration of Functional Laminin 332 in JEB Patients With Nonsense Mutations After Topical and Intravenous Gentamicin Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Junctional Epidermolysis Bullosa
Keywords: Herlitz
Laminin 332
Laminin beta 3
JEB
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2018-05-16
Enrollment: 6
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Herlitz junctional epidermolysis bullosa (H-JEB), an incurable, fatal, inherited skin disease, is caused by loss-of-function mutations in the LAMA3, LAMB3 or LAMC2 genes, resulting in loss of laminin 332 and poor epidermal-dermal adherence. Eighty percent of H-JEB patients have LAMB3 mutations and about 95% of these are nonsense mutations. The investigators recently demonstrated that gentamicin readily induced nonsense mutation readthrough and produced full-length laminin beta3 in several nonsense mutations tested. Importantly, the gentamicin-induced laminin beta3 restored laminin 332 assembly, secretion, and deposition into the dermal-epidermal junction (DEJ). Newly induced laminin 332 reversed abnormal H-JEB cellular phenotypes. Herein, the investigators propose the first clinical trial of gentamicin (by topical and intravenous administration) in JEB patients with nonsense mutations. The milestones will include restored laminin 332 and hemidesmosomes at the DEJ, improved wound closure, and the absence of significant gentamicin side effects.

Detailed description: Three subjects (adults and children of any age) will receive topical gentamicin to be applied to select skin sites.

Three subjects (adults and children of any age) will receive intravenous (IV) gentamicin infusions.

Patients will be assessed for Primary and Secondary endpoints during follow up visits.

Eligibility criteria: Inclusion Criteria:

1. JEB patients with nonsense mutations in the LAMB3 gene in either one or two alleles.

Exclusion Criteria:

1. JEB patients who do not have nonsense mutations in the LAMB3 gene in either allele.
2. Pre-existing known auditory impairment.
3. Pre-existing known renal impairment.
4. Pre-existing known allergies to aminoglycosides or sulfate compounds.
5. Pregnancy.

Primary outcomes:
measure: Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence.
timeFrame: 3 months
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 3 months
measure: Generation of new hemidesmosomes as assessed by electron microscopy.
timeFrame: 3 months
Secondary outcomes:
measure: Improved wound closure.
timeFrame: 3 months
measure: Reduction in blistering
timeFrame: 3 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
Study officials:
References:
citation: Mosallaei D, Hao M, Antaya RJ, Levian B, Kwong A, Cogan J, Hamilton C, Schwieger-Briel A, Tan C, Tang X, Woodley DT, Chen M. Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants. JAMA Dermatol. 2022 Apr 1;158(4):366-374. doi: 10.1001/jamadermatol.2021.5992.