Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations.,Molecular Therapy

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Gentamicin Induces Laminin 332 and Improves Wound Healing in Junctional Epidermolysis Bullosa Patients with Nonsense Mutations.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-03-17 , DOI: 10.1016/j.ymthe.2020.03.006
Andrew Kwong ₁ , Jon Cogan ₁ , Yingping Hou ₁ , Richard Antaya ₂ , Michelle Hao ₁ , Gene Kim ₁ , Vadim Lincoln ₁ , Qiuyang Chen ₁ , David T Woodley ₁ , Mei Chen ₁

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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.

中文翻译：

庆大霉素诱导层粘连蛋白 332 并改善具有无义突变的交界性大疱性表皮松解症患者的伤口愈合。

全身性严重交界性大疱性表皮松解症 (GS-JEB) 是一种无法治愈的致命性常染色体隐性遗传性水疱性皮肤病，由 LAMA3、LAMB3 或 LAMC2 基因突变引起。这些突变大多数是无义突变，会产生过早终止密码子，导致功能性层粘连蛋白 332（表皮-真皮粘附所需的蛋白质）的产生受损。庆大霉素可诱导无义突变的通读并恢复各种遗传疾病中的全长蛋白质。使用来自三名 GS-JEB 患者的原代角质形成细胞，我们发现庆大霉素诱导功能性层粘连蛋白 332 逆转与 JEB 相关的异常细胞表型。在随后涉及相同患者的开放标签试验中，我们检查了局部应用于开放性皮肤伤口的 0.5% 庆大霉素软膏是否可以促进无义突变读取并在患者皮肤中产生新的层粘连蛋白 332。庆大霉素治疗的伤口在真皮-表皮交界处表现出层粘连蛋白 332 表达增加至少 3 个月，并且与伤口闭合改善相关。外用庆大霉素没有任何不良副作用。新诱导的层粘连蛋白332并未在患者的血液或皮肤中产生抗层粘连蛋白332自身抗体。庆大霉素通读疗法可能是治疗具有无义突变的 GS-JEB 患者的方法。

更新日期：2020-03-17

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