JEB is an incurable blistering skin disorder with high infant mortality, often caused by nonsense variants in the genes that encode laminin 332, which holds the epidermis and dermis together, Dr. Mei Chen and Dr. David Woodley of the Keck School of Medicine at the University of Southern California, Los Angeles explained in an email to Reuters Health.
The nonsense mutations "cause the cellular machinery to prematurely stop translating the gene into the protein. This creates either no laminin 332 or a smaller truncated version of laminin 332 that is not functional," leading to blisters and open wounds, they said. "An old class of antibiotics called aminoglycosides...have the property of 'reading through' nonsense mutations and allowing the gene to translate fully and create a full-length, functional protein."
In a previous study, Drs. Chen, Woodley and colleagues showed that, compared with placebo, topical gentamicin generated new laminin 332 in JEB patients' skin and enhanced skin wound healing.
For the current study, published in JAMA Dermatology, the team gave five JEB pediatric patients (ages 3 months to 10 years; 80%, female; two intermediate and three severe cases) one course of IV gentamicin readthrough therapy. Participants were followed for 90 days.
Three patients received IV gentamicin 7.5 mg/kg daily for 14 days, and two received 10 mg/kg daily for 24 days.
The primary outcomes were change in laminin 332 expression in patients' skin, and safety - i.e., ototoxic or nephrotoxic effects, and autoimmune response.
Secondary outcomes included wound healing in monitored wounds and Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) scores.
All participants had increased laminin 332 in the dermal-epidermal junction. By one month, seven of nine wounds in patients receiving low-dose IV gentamicin and all wounds in patients receiving high-dose treatment showed at least 50% wound closure.
By three months, eight of nine wounds in those receiving low-dose treatment and all wounds in patients receiving high-dose treatment exhibited greater than 85% closure.
The three patients who were evaluated with EBDASI showed a decrease in total activity scores that met minimal clinically important differences one month after treatment.
All patients completed the study, with no detectable ototoxic effects, nephrotoxic effects, or anti-laminin 332 antibodies.
"Although long-term safety and efficacy requires further evaluation, a single cycle of intravenous gentamicin may be a safe and readily available therapy in the short term for this population of patients with JEB," the study authors state in the paper.
Drs. Chen and Woodley noted, "In addition to gentamicin and aminoglycosides, there are other medications and chemicals that can readthrough nonsense mutations in a manner even more powerful and more efficient than gentamicin and without the potential side effects on the kidneys and ears. Our current research direction is to find and characterize such agents and test them first in the laboratory and then in controlled clinical trials in patients."
Dr. Anna Bruckner of the University of Colorado Anschutz Medical Campus, Aurora, coauthor of a related editorial, told Reuters Health in an email that she is "cautiously optimistic" about the findings from this and other recent studies.
"While these results are encouraging, they need to be considered within the broader context of the overall scope of EB and more work needs to be done," she said. "We need to understand if changes in protein expression translate into improvements in physical function, overall health, and quality of life for patients. Future studies need to investigate the feasibility of using gentamicin repeatedly, which may have greater risk of toxicity and bacterial resistance."
SOURCE: https://bit.ly/3vO6nNC and https://bit.ly/35vQDUN JAMA Dermatology, online March 2, 2022.
By Marilynn Larkin
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