Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

Abstract

Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

“…only, leading to improved skin stability and quality-of-life (QoL) in 4/5 patients. However, in this study it did not postpone lethality [61]. Currently, two trials involving gentamicin treatment are running (NCT04140786, NCT03526159), aiming to increase laminin-332 and C7 expression in order to induce the generation of new hemidesmosomes and anchoring fibrils, respectively, monitored by immune-and electron microscopy of skin biopsies.…”

Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa

“…In fact, the outcome of these studies might pose the basis for a potential use of Hologene 5 also in some selected severe forms of JEB, which are characterized by undetectable expression of laminin 332 ( Kopp et al, 2005 ; Hammersen et al, 2016 ). In this respect, it has been shown that gentamicin can induce read-through of nonsense mutations and partially restore the expression of laminin 332 in patients with double null mutations in LAMB3 alleles, without triggering any immune reaction ( Hammersen et al, 2019 ; Kwong et al, 2020 ).…”

Clinical Perspectives of Gene-Targeted Therapies for Epidermolysis Bullosa

“…Beneficial impact on skin fragility was noted in four out of five patients, although the drug failed to prevent premature death. Early demise due to failure to thrive, airway obstruction and sepsis within the first 2 years of life is prototypic for this severe EB subtype [ 113 ]. Prospective studies to assess the safety and efficacy of intravenous gentamicin are ongoing (NCT03526159, NCT03392909, NCT04140786).…”