Optimization of Intravenous Gentamicin Treatment to Restore Functional Laminin 332 in JEB Patients With Nonsense Mutations

RATIONALE:

Herlitz junctional epidermolysis bullosa (H-JEB), an incurable and fatal inherited skin disease, is caused by loss-of-function mutations in LAMA3, LAMB3 and LAMC2. These mutations result in diminished laminin 332 and epidermal-dermal adherence. 85% of JEB patients have nonsense mutations in LAMA3, LAMB3, or LAMC2, suggesting that H-JEB is a prime therapeutic target for nonsense suppression therapy. The investigators recently demonstrated in three patients that topical gentamicin created new and stable laminin 332 at the dermal-epidermal junction (DEJ), and also improved wound closure and skin quality. Furthermore, these preliminary studies showed that intravenous gentamicin also induced laminin 332 and transiently improved patients' clinical outcomes. No untoward side effects occurred. The investigators propose to optimize the intravenous gentamicin regimen including dosage and infusion schedules to enhance the therapeutic outcome.

INTERVENTION:

There will be two study designs on JEB patients with nonsense mutation(s):

A. Short Term Daily IV Gentamicin Study: Three patients of any age with JEB caused by nonsense mutation(s) in the LAMA3 and LAMB3 genes will receive intravenous gentamicin (10 mgs/kg) daily for 24 days and then stop. Prior to treatment and at 1 month and 3 months post treatment, selected skin test sites will have skin biopsies and the specimens evaluated for the expression of laminin 332 at the dermal-epidermal junction by direct immunofluorescent staining of the skin. Safety parameters such as physical exam, review of systems, laboratory tests, audiometry, and renal function at the same time periods.