Infusions of Antibiotic Gentamicin Promote Wound Healing in JEB Trial
The antibiotic gentamicin, given via an infusion into the bloodstream, promoted wound closure and increased the production of laminin 332 in five children with junctional epidermolysis bullosa (JEB) in a small clinical trial.
Its researchers called for further study into this treatment as a potential long-term therapy for JEB.
Results were detailed in the study, “Molecular and Clinical Outcomes After Intravenous Gentamicin Treatment for Patients With Junctional Epidermolysis Bullosa Caused by Nonsense Variants,” published in the journal JAMA Dermatology.
“The 5 patients with JEB treated [in the trial] showed remarkable protein reexpression in the skin … that lasted over the 3-month period, and correlated with 85% wound closure in 93% of monitored wounds,” an international trio of experts wrote in an accompanying editorial.
JEB is mainly caused by mutations in genes that are needed to make laminin 332, an essential component of the structure that connects the skin’s outermost layer to inner layers. Most severe JEB-causing mutations are nonsense mutations, where a stop codon — a part of the genetic code that signals the end of a gene, sort of like a period at the end of a sentence — gets misplaced midway through the gene.
Recent research has suggested that gentamicin can promote the cell’s gene-reading machinary to “skip over” this abnormal stop signal, allowing the production of more laminin 332. Previous trial data also indicated that applying the antibiotic directly to skin wounds, as an ointment, increased laminin 332 levels and prompted wound healing in three JEB patients.
In this clinical trial (NCT03526159 and NCT04140786), conducted by the University of Southern California, five children with JEB were given gentamicin via intravenous infusions. They ranged in age from 3 months to 10 years; four were female and one was male. Two children were classified as having intermediate JEB, while the other three had severe JEB, and all had at least one confirmed nonsense mutation in the genes LAMA3 or LAMB3.
Three of the children received gentamicin at a low dose of 7.5 mg/kg daily for 14 days. The other two were treated at a higher dose of 10 mg/kg daily for 24 days.
Tissue analyses of participants’ skin showed quite low levels of laminin 332 at the study’s start (baseline measure).
One month after treatment, these levels had increased markedly: in one of the two children given the higher dose, levels of the three laminin 332 chains increased to 100%, 87.9%, and 98.5% of normal. In the other higher-dose child, levels increased to 57.5%, 73.0%, and 56.7% of normal one month later. Increases were also seen in the low-dose patients.
Nine skin wounds in the low-dose group were initially selected for monitoring. At one month post-treatment, seven of these wounds exhibited at least 50% closure. At three months, eight of the nine wounds had closed by at least 85%.
In the high-dose group, all wounds monitored showed at least 50% closure at month one post-treatment and 85% closure at three months.
Assessments of life quality, itch, and pain did not show clear trends following treatment. In the two children with intermediate JEB, who were old enough to complete assessments about their subjective experiences, assessments indicated “improvements in their emotions (worry, frustration, embarrassment, and depression) and functioning (interpersonal interactions, showing affection, and daily activities) that was sustained up to the end of the trial period,” the researchers wrote.
The therapy was safe overall, with no side effects reported. None of the patients showed signs of an immune response against laminin 332 “despite the induction” of this connective component of the skin, the researchers wrote.
“The safety of any emerging therapy is paramount, and it is heartening to note no adverse effects were seen,” according to the editorial’s authors.
Nonetheless, they cautioned that this and other studies of gentamicin in JEB have been comparatively short-term, stressing a need for longer studies.
“To modify their natural history, a treatment such as gentamicin would ideally be started at an early age and repeated at regular intervals to stabilize the condition over a patient’s lifetime. Stopping therapy would presumably lead to a resumption in disease progression,” they wrote in the editorial.
“Because therapies such as gentamicin were not designed for long-term use, additional studies on the feasibility, possible accumulative toxic effects, risk of microbial resistance … as well as benefits of longer-term therapy are needed before this approach can be fully endorsed.”