Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa
Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa
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DOI：
10.1016/j.jid.2017.05.011
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发表时间：
2017-09-01
影响因子：
6.5
通讯作者：
South, Andrew P.
中科院分区：
文献类型：
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作者：
Atanasova, Velina S.;Jiang, Qiujie;South, Andrew P.
隐性营养不良大疱性表皮松解症（RDEB）是一种罕见的单基因起泡疾病，由缺乏功能性VII型胶原蛋白引起，导致皮肤脆弱和随后的创伤性表皮与真皮分离。总共46%的RDEB患者在COL7A1中至少有一个过早终止密码子（PTC）突变，先前的研究表明，氨基糖苷能够通过诱导PTC位点的“通读”和氨基酸的结合来克服RDEB PTC突变。然而，氨基糖苷的毒性可能会阻碍临床的广泛应用。在这里，fda批准的药物amlexanox被测试其读取来自RDEB患者的细胞中PTC突变的能力。12个不同的PTC等位基因中有8个对治疗有反应，并产生全长蛋白，在某些情况下，与正常对照相比，产生全长蛋白的比例超过50%。VII型胶原在细胞培养基中很容易检测到，在器官型皮肤培养中也定位于真皮-表皮交界处。Amlexanox增加COL7A1转录和UPF-1的磷酸化，UPF-1是一种与无义介导的mRNA衰变相关的RNA解旋酶，这表明Amlexanox抑制RDEB患者细胞中无义介导的mRNA衰变，这些患者对穿透治疗有反应。这项临床前研究证明了将氨lexanox重新用于治疗COL7A1中携带PTC突变的RDEB患者的潜力。
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder caused by the lack of functional type VII collagen, leading to skin fragility and subsequent trauma-induced separation of the epidermis from the underlying dermis. A total of 46% of patients with RDEB harbor at least one premature termination codon (PTC) mutation in COL7A1, and previous studies have shown that aminoglycosides are able to overcome RDEB PTC mutations by inducing "read-through" and incorporation of an amino acid at the PTC site. However, aminoglycoside toxicity will likely prevent widespread clinical application. Here the FDA-approved drug amlexanox was tested for its ability to read-through PTC mutations in cells derived from patients with RDEB. Eight of 12 different PTC alleles responded to treatment and produced full length protein, in some cases more than 50% relative to normal controls. Read-through type VII collagen was readily detectable in cell culture media and also localized to the dermal-epidermal junction in organotypic skin culture. Amlexanox increased COL7A1 transcript and the phosphorylation of UPF-1, an RNA helicase associated with nonsense-mediated mRNA decay, suggesting that amlexanox inhibits nonsense-mediated mRNA decay in cells from patients with RDEB that respond to read-through treatment. This preclinical study demonstrates the potential of repurposing amlexanox for the treatment of patients with RDEB harboring PTC mutation in COL7A1.