Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations
| Autor: | David T. Woodley, Michelle Hao, Yingping Hou, Vadim Lincoln, Qiuyang Chen, Jon Cogan, Mei Chen, Andrew Kwong, Richard J. Antaya, Gene Kim |
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| Rok vydání: | 2020 |
| Předmět: |
Keratinocytes
Male Cell Survival Nonsense mutation Administration Cutaneous 03 medical and health sciences 0302 clinical medicine Laminin Drug Discovery Genetics medicine Humans Child Molecular Biology Gene Cells Cultured Skin 030304 developmental biology Pharmacology Wound Healing 0303 health sciences integumentary system biology business.industry Autoantibody Infant Phenotype Anti-Bacterial Agents Treatment Outcome Codon Nonsense Child Preschool 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Original Article Female Gentamicin Gentamicins Epidermolysis Bullosa Junctional business Wound healing Cell Adhesion Molecules Junctional epidermolysis bullosa (veterinary medicine) Follow-Up Studies Signal Transduction medicine.drug |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0016 |
| Popis: | Generalized severe junctional epidermolysis bullosa (GS-JEB) is an incurable and fatal autosomal recessively inherited blistering skin disease caused by mutations in the LAMA3, LAMB3, or LAMC2 genes. Most of these mutations are nonsense mutations that create premature termination codons that lead to impaired production of functional laminin 332, a protein needed for epidermal-dermal adherence. Gentamicin induces readthrough of nonsense mutations and restores the full-length protein in various genetic diseases. Using primary keratinocytes from three GS-JEB patients, we showed that gentamicin induced functional laminin 332 that reversed a JEB-associated, abnormal cell phenotype. In a subsequent open-label trial involving the same patients, we examined whether 0.5% gentamicin ointment applied topically to open skin wounds could promote nonsense mutation readthrough and create new laminin 332 in the patients’ skin. Gentamicin-treated wounds exhibited increased expression of laminin 332 at the dermal-epidermal junction for at least 3 months and were associated with improved wound closure. There were no untoward side effects from topical gentamicin. The newly induced laminin 332 did not generate anti-laminin 332 autoantibodies in either the patients’ blood or skin. Gentamicin readthrough therapy may be a treatment for GS-JEB patients with nonsense mutations. Graphical Abstract Many patients with junctional epidermolysis bullosa, a genetic skin disease, lack laminin 332 protein due to nonsense mutations in laminin 332 genes. This paper reports that topical gentamicin suppresses nonsense mutations, induces new laminin 332, and improves wound closure. Gentamicin may provide a novel, readily available therapy for these patients. |
| Databáze: | OpenAIRE |
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