Background: Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable widespread blistering skin disorder caused by mutations in the gene encoding for type VII collagen (C7), the major component of anchoring fibrils.
Objective: To evaluate the efficacy and safety of intravenous (IV) gentamicin-readthrough therapy in patients with RDEB harboring nonsense mutations. Primary outcomes were increased expression of C7 in patients' skin and assessments for safety (ototoxicity, nephrotoxicity, autoimmune response). Secondary outcomes included measuring wound healing in target wounds and assessment by a validated Epidermolysis Bullosa Disease and Activity Scarring Index (EBDASI) scoring system.
Methods: An open-label pilot trial assessing two different regimens of IV gentamicin between August 2018 and March 2020 with follow-up through 180 days post-treatment. Three RDEB patients with confirmed nonsense mutations in COL7A1 in either one or two alleles and decreased baseline expression of C7 at the dermal-epidermal junction (DEJ) of their skin participated in the study. Three patients received gentamicin at 7.5 mg/kg daily for 14 days and two of three patients further received 7.5 mg/kg IV gentamicin twice weekly for 12 weeks.Patients who had pre-existing auditory or renal impairment, were currently using ototoxic or nephrotoxic medications, or had allergies to aminoglycosides or sulfate compounds were excluded.
Results: After gentamicin treatment, skin biopsies from all three patients (ages ranging 18-28 years) exhibited increased C7 in their DEJ. With both regimens, the new C7 persisted at least six months post-treatment. At one and three-months post-treatment, 100% of the monitored wounds exhibited greater than 85% closure. Both IV gentamicin infusion regimens decreased EBDASI total activity scores. Of all patients assessed with the EBDASI, all patients exhibited decreased total activity scores three-month post-treatment. All three patients completed the study, and no adverse effects or anti-C7 antibodies were detected.
Conclusions: IV gentamicin induced readthrough of nonsense mutations in RDEB patients and restored functional C7 in their skin, enhanced wound healing, and improved clinical parameters. IV gentamicin may be a safe, efficacious, low cost, and readily available therapy in this population of RDEB patients.
Trial registration: Clinicaltrials.gov Identifiers: NCT03392909.
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