Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants

Abstract

IMPORTANCE Junctional epidermolysis bullosa (JEB) is an incurable blistering skin disorder with high infant mortality often caused by nonsense variants in the genes that encode laminin 332.OBJECTIVE To evaluate the safety and outcomes following intravenous gentamicin readthrough therapy and subsequent laminin 332 expression in patients with JEB. DESIGN, SETTING, AND PARTICIPANTSThis open-label, pilot nonrandomized clinical trial assessed 1 course of low-or high-dose intravenous gentamicin, including follow-up at 30 and 90 days after treatment. Five pediatric patients with JEB (2 with intermediate JEB and 3 with severe JEB) and confirmed nonsense variants in LAMA3 or LAMB3 in 1 or 2 alleles and decreased expression of laminin 332 at the dermal-epidermal junction of their skin participated in the study, which was performed at a single institution in collaboration with physicians and home infusion services near the patients from

Understanding the Potential Promise and Pitfalls of Intravenous Gentamicin as a Therapy for Epidermolysis Bullosa

“…Although immunofluorescence microscopy (IFM) is most often used to assess protein expression, this method does not evaluate protein functionality. The 5 patients with JEB treated by Mosallaei and colleagues showed remarkable protein reexpression in the skin on IFM that lasted over the 3-month period, and correlated with 85% wound closure in 93% of monitored wounds. The adult woman with EBS-MD treated by Martínez-Santamaría and colleagues had mild mucocutaneous involvement but marked muscular involvement when gentamicin therapy was initiated.…”

“…Although demonstrating a relevant change in the target biomarkers, laminin 332 and plectin, is important in these proof-of-concept studies, demonstrating clinically meaningful benefit that correlates with biomarker improvement is imperative for clinical trials. Mosallaei and colleagues 6 assessed changes in pain, itch, and quality of life. However, these data were incomplete and variable, making the interpretation of clinical relevance for the patients difficult.…”

“…These reports highlight the heterogenous nature of EB, which makes assessing outcomes especially challenging. Mosallaei and colleagues and Martínez-Santamaría and colleagues both used the EB Disease Activity and Scarring Index (EBDASI) as an outcome measure, but the small changes seen in the overall scores are difficult to interpret in the absence of a comparator or control. Because signs and symptoms of EB can fluctuate in a patient over time, establishing a baseline prior to assessing for change is imperative in a rigorous clinical trial.…”

“…In this issue of JAMA Dermatology , 2 groups of investigators report the short-term outcomes of intravenous gentamicin as a readthrough therapy for junctional EB (JEB) and EB simplex with muscular dystrophy (EBS-MD). Mosallaei and colleagues evaluated 5 pediatric patients with intermediate or severe JEB owing to nonsense variants in LAMA3 and LAMB3 , whereas Martínez-Santamaría and colleagues observed 1 adult with EBS-MD owing to a homozygous nonsense variant in PLEC . Although both groups demonstrated that gentamicin induced or augmented the expression of the absent or deficient affected proteins and was well tolerated, the clinical relevance of this intervention is more difficult to estimate.…”

Treatment With Ataluren for Wound Healing and Health Complications in a Patient With Junctional Epidermolysis Bullosa

“…Gentamicin, like ataluren, promotes ribosomal PTC readthrough and has shown promise in JEB treatment. 5,6 However, topical gentamicin use is not practical on mucosal surfaces or extensive wound areas, and its systemic use is restricted by nephrotoxic effects, ototoxic effects, and lack of oral availability. In contrast to gentamicin, ataluren is orally available and has no significant toxic effects; thus, it can be used continuously.…”