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Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable and inherited mechano-bullous disease of the skin characterized by skin fragility, blister formation, and chronic wounds. RDEB is caused by mutations in the COL7A1 gene encoding type VII collagen (C7), the major component of anchoring fibrils (AFs) that anchor the epidermis to the dermis. AFs are attenuated, diminutive, or absent in RDEB. There is no effective treatment for RDEB except palliative measures and supportive wound care. Based on encouraging in vitro and in vivo RDEB data, the proposed study will assess the safety and efficacy of IV gentamicin in RDEB patients with nonsense mutations.
This phase I/II clinical trial tests the short and long term safety and efficacy of open-label intravenous (IV) gentamicin in treating patients with recessive dystrophic epidermolysis bullosa (RDEB) due to nonsense mutations in their COL7A1 gene that encodes for type VII collagen (C7). The investigators hypothesize that the administration of intravenous gentamicin will induce premature stop codons (PTC) read-through, create new type VII collagen and anchoring fibrils at the epidermal-dermal junction of the patients and improve clinical outcomes at multiple skin sites simultaneously without major side effects. It will administer IV gentamicin to 6 RDEB patients daily for 14 days or twice weekly for 3 months and: (i) determine the percentage increase of C7 and AFs in the DEJ of the patients' skin before and after treatment, (ii) determine the post-treatment sustainability of new C7 and AFs in the patients' skin, (iii) determine if this regimen is safe in this patient population, and (iv) determine if it improves the patient's skin lesions and their quality of life. This proposed clinical trial could very well lead to the first novel and non-invasive treatment of RDEB patients carrying nonsense mutations. A successful outcome would have profound therapeutic potential for the 30% of RDEB patients caused by nonsense mutations.
- 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.
- 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.
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
University of Southern California, Los Angeles, California, United States 90033