Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants

Abstract

IMPORTANCEEpidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is an autosomal recessive disorder caused by pathogenic variants in PLEC1, which encodes plectin. It is characterized by mild mucocutaneous fragility and blistering and muscle weakness. Translational readthrough-inducing drugs, such as repurposed aminoglycoside antibiotics, may represent a valuable therapeutic alternative for untreatable rare diseases caused by nonsense variants. OBJECTIVE To evaluate whether systemic gentamicin, at a dose of 7.5 mg/kg/d for 14 consecutive days, is clinically beneficial in a patient with EBS-MD. DESIGN, SETTING, AND PARTICIPANTSA single patient in Madrid, Spain, received 2 treatment courses with gentamicin on July 2019 and February 2020 with a follow-up period of 120 and 150 days, respectively. RESULTSIn this case report of a woman in her 30s with EBS-MD, before gentamicin treatment, the patient had mucocutaneous involvement, skeletal and respiratory muscle weakness, and myalgia that negatively affected her quality of life. Outcomes were evaluated with extensive laboratory tests and clinical scales. No nephrotoxic or ototoxic effects were detected after intravenous gentamicin administration. Gentamicin treatment was followed by plectin expression in the skin for at least 5 months. Although minimal changes were noted in skeletal muscle function (as measured by the Hammersmith functional motor scale and its expanded version: 6/40 to 7/40 and from 10/66 to 11/66, respectively) and respiratory musculature (maximal inspiratory and expiratory pressures D0 vs D16, MIP: 2.86 vs 3.63 KPa and MEP: 2.93 vs 4.63 KPa), myalgia disappeared (VAS dropped from 6 to 0), and quality of life improved (EuroQoL-5D-3L pain and anxiety dropped from 2 to 1). CONCLUSIONS AND RELEVANCEThe findings of this single case report suggest that gentamicin treatment may help suppress PLEC1 premature termination codons and induce plectin expression in EBS-MD primary keratinocytes and skin. Our study suggests that gentamicin may play an important role in treating EBS-MD owing to nonsense variants.

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

“…However, these data were incomplete and variable, making the interpretation of clinical relevance for the patients difficult. Martínez-Santamaría and colleagues showed modest, albeit short-lived improvements in neuromuscular and ventilatory function and a reduction in muscle pain in their patient. No improvement in the performance of core daily activities was documented in either study.…”

“…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. She received two 14-day courses of 7.5 mg/kg/d of intravenous gentamicin with 7 months in between courses.…”

“…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.…”

Mutation update: The spectra of PLEC sequence variants and related plectinopathies

“…Gentamicin is an aminoglycoside, which beyond its antimicrobial actions can read through PTCs and has been tested in several genetic diseases. In fact, a recent study reported that systemic gentamicin in an EBS‐MD patient led to an improvement in daily quality of life, strength, mobility, maximal inspiratory and expiratory pressures, and decreased mucosal blistering (Martinez‐Santamaria et al, 2022). Additionally, they found that keratinocytes cultured with gentamicin had increased plectin expression.…”