In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions

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 for the first time a 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 was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed 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. 23 samples were analyzed. WT animal RNA expression profiles were compared to animals treated with the standard of care for HT1: NTBC, as well as LV-FAH gene therapy, and the negative control, which was cycled on and off the standard of care NTBC. Samples were also analyzed for integration profiles of LV-FAH from various tissues in the LV-FAH treated animals. ****Please note that raw data for the '282 NTBC RNA-Seq', '266 RNA-seq (RLI)' samples are unavailable and thus are not included in the records****

针对遗传性1型酪氨酸血症（hereditary tyrosinemia type 1, HT1）的常规治疗方案采用2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮（2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC），虽可延缓病情进展，但部分病例仍无法阻断疾病向肝纤维化、肝衰竭及致癌通路激活的方向发展。本研究首次证实，在HT1猪模型中，通过体内直接递送靶向表达人源延胡索酰乙酰乙酸水解酶（fumarylacetoacetate hydrolase, FAH）转基因的治疗性慢病毒载体（lentiviral vector, LV），可实现HT1的治愈。该疗法耐受性良好，可在HT1染病猪体内稳定长期表达FAH。基因组整合行为呈现良性特征，与NTBC治疗组或未接受治疗的患病动物相比，其后续纤维化及致癌相关基因的表达模式与野生型动物无显著差异。事实上，体内慢病毒载体给药后的表型与基因组数据显示，该疗法相较于包括体外细胞疗法在内的其他治疗手段具有比较优势，因此支持该方案的临床转化应用。本研究共分析23份样本。将野生型（wild-type, WT）动物的RNA表达谱与接受HT1标准治疗方案NTBC的动物、LV-FAH基因治疗动物，以及在标准治疗NTBC间间歇给药的阴性对照组动物进行了对比。此外，还针对LV-FAH治疗组动物的不同组织中LV-FAH的整合特征进行了分析。请注意："282 NTBC RNA-Seq"、"266 RNA-seq (RLI)"样本的原始数据暂未公开，因此未纳入本数据集记录中。