SG07 Real-world experience with the use of intravenous gentamicin to induce nonsense mutation readthrough in an adult patient with recessive dystrophic epidermolysis bullosa

Abstract Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease characterized by extensive mucocutaneous blistering, chronic wounds and multisystem sequelae. It arises as a result of biallelic pathogenic variants in the COL7A1 gene, encoding type VII collagen (C7), an integral protein of anchoring fibrils at the dermoepidermal junction in the skin. Up to 30% of variants are nonsense, resulting in premature termination codons (PTCs) in DNA and subsequent mRNA decay and little or no functional C7. Nonsense-mediated readthrough therapy utilizes the ability of aminoglycosides to facilitate readthrough of PTCs and therefore the translation of functional C7. A pilot trial in the USA demonstrated intravenous (IV) gentamicin-induced nonsense mutation readthrough in COL7A1 and restored functional C7 expression in the skin of three patients with RDEB. The aim of the current study was to evaluate the clinical efficacy and safety of IV gentamicin therapy in an 18-year-old woman with severe RDEB, in a specialist centre in the UK. Gentamicin 5 mg kg−1 per day IV was administered for 14 consecutive days during an inpatient stay. Trough gentamicin levels were taken every 48 h to ensure drug levels were < 1 mg L−1 prior to dosing. Disease severity assessment tools were used to evaluate the efficacy of treatment at baseline and at 2, 6 and 15 weeks after initiation of treatment. This included assessment of wound closure, Epidermolysis Bullosa Disease Activity and Scarring Index, Quality of Life in Epidermolysis Bullosa (QOLEB), visual analogue scale for background and procedural pain and Leven Itch Scale. Safety assessments were performed to monitor for nephrotoxicity and ototoxicity. Improvements in wound closure of approximately 20%, 35% and 50% were seen at weeks 2, 6 and 15 post-treatment, respectively. There was no significant reduction in QOLEB scores. Background pain scores had reduced by 50% by week 6 and this was maintained at week 15; however, there was no change to reported procedural pain. Frequency-of-itch scores did not reduce across any timepoint; however, itch distress had reduced by 68% by week 15. There were no adverse events to treatment. IV gentamicin may be a safe, efficacious, low-cost and readily available treatment for patients with RDEB. Further real-world practice is necessary to optimize the dosing schedule and evaluate longer term outcomes on wound closure and quality of life, in a larger patient population.