Levian Brandon, Hou Yingping, Tang Xin, Bainvoll Liat, Zheng Kate, Badarinarayana Vasu, Aghamohammadzadeh Soheil, Chen Mei
Department of Dermatology, The Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Eloxx Pharmaceuticals, Watertown, MA, USA.
Mol Ther Nucleic Acids. 2024 Sep 10;35(4):102334. doi: 10.1016/j.omtn.2024.102334. eCollection 2024 Dec 10.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are lethal blistering skin disorders resulting from mutations in genes coding for type VII collagen () and laminin 332 (, , or ), respectively. In RDEB, 25% of patients harbor nonsense mutations causing premature termination codons (PTCs). In JEB, a majority of mutations in are nonsense mutations (80%). ELX-02, an aminoglycoside analog, has demonstrated superior PTC readthrough activity and lower toxicity compared to gentamicin in various genetic disorders. This study investigated the ability of ELX-02 to suppress PTCs and promote the expression of C7 and laminin 332 in primary RDEB keratinocytes/fibroblasts and primary JEB keratinocytes harboring nonsense mutations. ELX-02 induced a dose-dependent production of C7 or laminin β3 that surpassed the results achieved with gentamicin. ELX-02 reversed RDEB and JEB cellular hypermotility and improved poor cell-substratum adhesion in JEB cells. Importantly, ELX-02-induced C7 and laminin 332 localized to the dermal-epidermal junction. This is the first study demonstrating that ELX-02 can induce PTC readthrough and restore functional C7 and laminin 332 in RDEB and JEB caused by nonsense mutations. Therefore, ELX-02 may offer a novel and safe therapy for RDEB, JEB, and other inherited skin diseases caused by nonsense mutations.
隐性营养不良性大疱性表皮松解症（RDEB）和交界性大疱性表皮松解症（JEB）是致死性水疱性皮肤病，分别由编码VII型胶原蛋白（）和层粘连蛋白332（、或）的基因突变引起。在RDEB中，25%的患者携带导致过早终止密码子（PTC）的无义突变。在JEB中，大多数的突变是无义突变（80%）。与庆大霉素相比，氨基糖苷类似物ELX - 02在各种遗传疾病中表现出更强的PTC通读活性和更低的毒性。本研究调查了ELX - 02在原发性RDEB角质形成细胞/成纤维细胞以及携带无义突变的原发性JEB角质形成细胞中抑制PTC并促进C7和层粘连蛋白332表达的能力。ELX - 02诱导产生剂量依赖性的C7或层粘连蛋白β3，其效果超过了庆大霉素。ELX - 02逆转了RDEB和JEB细胞的高运动性，并改善了JEB细胞中不良的细胞与基质黏附。重要的是，ELX - 02诱导产生的C7和层粘连蛋白332定位于真皮 - 表皮交界处。这是第一项证明ELX - 02可诱导PTC通读并在由无义突变引起的RDEB和JEB中恢复功能性C7和层粘连蛋白332的研究。因此，ELX - 02可能为RDEB、JEB以及其他由无义突变引起的遗传性皮肤病提供一种新的安全治疗方法。
