Greig Jenny A, Nordin Jayme M L, Smith Melanie K, Ashley Scott N, Draper Christine, Zhu Yanqing, Bell Peter, Buza Elizabeth L, Wilson James M
Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Hum Gene Ther Clin Dev. 2019 Mar;30(1):29-39. doi: 10.1089/humc.2018.219. Epub 2019 Feb 25.
Wilson disease (WD), an autosomal recessive disease caused by mutations in a copper-transporting P-type ATPase (Atp7b), causes severe liver damage. This disease is currently treated with the lifelong use of copper chelation therapy, which has side effects and does not fix copper metabolism. Here, we thoroughly characterized a mouse model of WD, the toxic milk mouse, and used the model to test a gene therapy approach for treating WD. WD mice accumulated copper in the liver from birth; severe copper accumulation and concurrent liver disease were evident by 2 months of age. Intravenously administering an adeno-associated viral (AAV) 8 vector expressing a codon-optimized version of the human ATP7B transgene into 2-month-old WD mice significantly decreased liver copper levels compared with age-matched, uninjected, WD mice. We also observed a significant dose-dependent decrease in liver disease. Male mice injected with 10 genome copies of AAV8 vector showed only mild histopathological findings with a complete lack of liver fibrosis. Therefore, we conclude that administering gene therapy at the early stages of disease onset is a promising approach for reducing liver damage and correcting copper metabolism in WD.
威尔逊病（WD）是一种由铜转运P型ATP酶（Atp7b）突变引起的常染色体隐性疾病，会导致严重的肝脏损伤。目前，这种疾病通过终身使用铜螯合疗法进行治疗，该疗法有副作用且无法修复铜代谢。在此，我们全面表征了WD的小鼠模型——毒乳小鼠，并使用该模型测试治疗WD的基因治疗方法。WD小鼠从出生起就在肝脏中积累铜；到2月龄时，明显出现严重的铜积累和并发肝病。将表达人ATP7B转基因密码子优化版本的腺相关病毒（AAV）8载体静脉注射到2月龄的WD小鼠体内，与年龄匹配的未注射WD小鼠相比，显著降低了肝脏铜水平。我们还观察到肝病有显著的剂量依赖性降低。注射10个基因组拷贝AAV8载体的雄性小鼠仅表现出轻微的组织病理学结果，完全没有肝纤维化。因此，我们得出结论，在疾病发作早期进行基因治疗是减少WD肝脏损伤和纠正铜代谢的一种有前景的方法。
