Gentamicin for Junctional Epidermolysis Bullosa

NCT03526159 | Recruiting Phase 1 FDA Drug

• 1 other identifier: HS-18-00290
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Junctional Epidermolysis Bullosa

Keywords

Herlitz; Laminin 332; Laminin beta 3; JEB

Outcome Measures

Primary Outcomes (3)

• Increased laminin beta 3 / laminin 332 expression as assessed by immunofluorescence.

  New or increased staining of the target protein, laminin 332, in sections of skin biopsies obtained during follow-up visits in comparison with baseline biopsies. Five micron cryosections will be probed with three different antibodies against laminin 332. Patient samples along with normal control samples will be compared. Mean fluorescence intensity will be calculated for each sample and antibody using ImageJ software. Percent expression relative to normal human skin (set to 100%) will be calculated for each patient sample. Any statistically significant increase in (p value \< 0.05) over baseline will be considered improvement.

  3 months

• Incidence of Treatment-Emergent Adverse Events

  The total number of adverse events and serious adverse events will be recorded and enumerated for each study participant. Gentamicin in high doses is associated with ototoxicity and nephrotoxicity. Audiometry and creatinine clearance tests will be performed throughout the study to monitor for the emergence of any treatment-related adverse events. In addition, as this treatment may result in the production of a protein that is hasn't been present in the patient's system, commercial ELISA tests will be performed on serum samples to test for the emergence of circulating anti-laminin 332 antibodies. Adverse events include a decline of \>15 dB on pure tone audiometry at 2 consecutive frequencies, creatinine clearance \<60ml/min, presence of antibodies to laminin 332, and for IV gentamicin recipients, serum gentamicin peak levels above 40 ug/ml and trough levels above 2 ug/ml.

  3 months

• Generation of new hemidesmosomes as assessed by electron microscopy.

  Any new hemidesmosomes detected by electron microscopy in post-treatment skin biopsies will be enumerated and compared to baseline.

  3 months

Secondary Outcomes (2)

• Improved wound closure.

  3 months

• Reduction in blistering

  3 months

Study Arms (1)

Gentamicin Sulfate

EXPERIMENTAL

IV Arm: 7.5 mg/kg gentamicin once daily for 14 days. Topical Arm: 0.5% gentamicin ointment applied twice daily for 14 days to selected skin sites.

Drug: Gentamicin Sulfate

Interventions

Gentamicin Sulfate DRUG

Gentamicin (formulated as gentamicin sulfate) is a well-known, well-characterized antibiotic that has been used for four decades as a treatment against gram negative bacteria. It, like other aminoglycoside antibiotics, has the well documented added potential to facilitate readthrough of premature termination codons in eukaryotic cells and organisms.

Also known as: Gentamicin

Gentamicin Sulfate

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• University of Southern California: lead

Study Sites (1)

University of Southern California

Los Angeles, California, 90033, United States

RECRUITING

Related Publications (1)

• 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.

  PMID: 35234826 DERIVED

MeSH Terms

Conditions

Epidermolysis Bullosa, Junctional

Interventions

Gentamicins

Condition Hierarchy (Ancestors)

Epidermolysis Bullosa; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vesiculobullous

Intervention Hierarchy (Ancestors)

Aminoglycosides; Glycosides; Carbohydrates

Central Study Contacts

Mei Chen, Ph.D.

CONTACT

3238650621; chenm@usc.edu

David Woodley, M.D.

CONTACT

3238650956; dwoodley@usc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 17, 2018
• First Posted: May 16, 2018
• Study Start: June 1, 2018
• Primary Completion: July 30, 2020
• Study Completion: August 31, 2020
• Last Updated: April 7, 2020

Record last verified: 2020-04

Locations

US (1)