In a pilot study, , Michelle Hao said at the virtual annual meeting of the American Academy of Dermatology.
Serial skin biopsies and immunofluorescent staining demonstrated the mechanism of benefit: The aminoglycoside promoted creation of new full-length functional collagen fibrils at the dermal-epidermal junction in affected patients, added Ms. Hao, a medical student at the University of Southern California, Los Angeles.
“Glycoside-mediated nonsense suppression therapy may provide a novel, low cost, and readily available treatment for RDEB [recessive dystrophic epidermolysis bullosa] patients harboring nonsense mutations,” she declared.
RDEB is a rare, incurable, life-threatening genetic skin disease which manifests as severe skin fragility and widespread blistering. The disease is caused by mutations in a gene coding for collagen type VII alpha 1 (COL7A1), the building block for the anchoring fibrils responsible for dermal-epidermal adherence. Roughly 30% of COL7A1 mutations are nonsense mutations, which result in truncated, nonfunctional collagen type VII.
Ms. Hao and her senior coinvestigators have previously shown that aminoglycoside antibiotics can override nonsense mutations to produce full-length, functioning protein. Indeed, they demonstrated that topical gentamicin in particular induces formation of new collagen type VII and improves wound closure in RDEB patients with nonsense mutations. However, RDEB skin lesions are so widespread that topical therapy becomes impractical. This was the impetus for the phase 1/2 clinical trial of IV gentamicin.
The open-label study included four patients with RDEB with nonsense mutations. All participants received IV gentamicin at 7.5 mg/kg/day for 2 weeks. Two of the four patients then got additional twice-weekly infusions at the same dose for another 3 months. Skin biopsies were obtained from two prospectively monitored open erosive wound sites and two intact skin sites at baseline and 1 and 3 months after treatment.
The primary endpoint was evidence of new collagen type VII at the dermal-epidermal junction post treatment. At baseline, patients averaged only 2% of the amount present in normal skin. One month post treatment, all four patients showed significant gains in expression of functioning collagen type VII, with levels 30%-130% of what’s present in normal skin. This effect proved durable 3 months post treatment.
At the same visits when biopsies were obtained, participants were assessed regarding wound closure, disease activity as measured using the validated Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), and quality of life as reflected in Skindex-16 scores. All four patients showed improved wound closure at 1 and 3 months post treatment at the monitored sites, as well as better EBDASI and Skindex-16 Symptoms and Skindex-16 Emotion scores, Ms. Hao continued.
Safety assessments revealed no evidence of oto- or nephrotoxicity in the gentamicin-treated patients. And no one developed autoantibodies to collagen type VII in skin or sera in response to the aminoglycoside-induced creation of new collagen type VII.
Ms. Hao said preliminary analysis of the study data suggests that the more convenient schedule of twice-weekly IV gentamicin was as effective with regard to wound closure as daily infusion therapy.
She reported having no financial conflicts regarding the study, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the EB Research Partnership, and the EB Research Foundation.