Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Nat Commun. 2022 Aug 25;13(1):5012. doi: 10.1038/s41467-022-32576-7.
Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well tolerated and provides stable long-term expression of FAH in pigs with HT1. Genomic integration displays a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.
传统的 2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮（NTBC）治疗 1 型遗传性酪氨酸血症（HT1）可延迟，但在某些情况下无法阻止疾病进展为肝纤维化、肝功能衰竭和致癌途径的激活。在这里，我们通过直接向 HT1 的猪模型体内给予靶向表达人延胡索酰乙酰乙酸水解酶（FAH）转基因的治疗性慢病毒载体，证明了 HT1 的治愈。这种治疗方法耐受性良好，可在 HT1 猪体内稳定长期表达 FAH。基因组整合显示良性特征，随后的纤维化和致癌基因表达模式与野生型动物相似，与 NTBC 治疗或未治疗的患病动物相比。事实上，体内慢病毒载体给药后的表型和基因组数据表明，与其他治疗方法（包括体外细胞治疗）相比具有比较优势，因此支持该方法的临床应用。
