Gentamicin for Junctional Epidermolysis Bullosa
| Status: | Recruiting |
|---|---|
| Conditions: | Skin and Soft Tissue Infections |
| Therapuetic Areas: | Dermatology / Plastic Surgery |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 12/22/2018 |
| Start Date: | June 1, 2018 |
| End Date: | July 31, 2020 |
| Contact: | Mei Chen, Ph.D. |
| Email: | chenm@usc.edu |
| Phone: | 3238650621 |
A Pilot Study of the Restoration of Functional Laminin 332 in JEB Patients With Nonsense Mutations After Topical and Intravenous Gentamicin Treatment
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.
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.
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.
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.
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.
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