Gene Therapy Center, University of Minnesota, Minneapolis, MN, USA.
Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
Mol Ther. 2019 Jan 2;27(1):178-187. doi: 10.1016/j.ymthe.2018.10.018. Epub 2018 Nov 1.
Mucopolysaccharidosis type I (MPS I) is a severe disease due to deficiency of the lysosomal hydrolase α-L-iduronidase (IDUA) and the subsequent accumulation of the glycosaminoglycans (GAG), leading to progressive, systemic disease and a shortened lifespan. Current treatment options consist of hematopoietic stem cell transplantation, which carries significant mortality and morbidity risk, and enzyme replacement therapy, which requires lifelong infusions of replacement enzyme; neither provides adequate therapy, even in combination. A novel in vivo genome-editing approach is described in the murine model of Hurler syndrome. A corrective copy of the IDUA gene is inserted at the albumin locus in hepatocytes, leading to sustained enzyme expression, secretion from the liver into circulation, and subsequent uptake systemically at levels sufficient for correction of metabolic disease (GAG substrate accumulation) and prevention of neurobehavioral deficits in MPS I mice. This study serves as a proof-of-concept for this platform-based approach that should be broadly applicable to the treatment of a wide array of monogenic diseases.
黏多糖贮积症 I 型（MPS I）是一种严重的疾病，由于溶酶体水解酶α-L-艾杜糖苷酸酶（IDUA）的缺乏，以及随后糖胺聚糖（GAG）的积累，导致进行性、全身性疾病和寿命缩短。目前的治疗选择包括造血干细胞移植，这具有显著的死亡率和发病率风险，和酶替代疗法，这需要终身输注替代酶；即使联合使用，也不能提供足够的治疗效果。在Hurler 综合征的小鼠模型中描述了一种新型的体内基因组编辑方法。IDUA 基因的校正拷贝被插入到肝细胞的白蛋白基因座，导致持续的酶表达、从肝脏分泌到循环中，并随后在足以纠正代谢疾病（GAG 底物积累）和预防 MPS I 小鼠神经行为缺陷的全身水平上被系统性摄取。这项研究为这种基于平台的方法提供了概念验证，该方法应该广泛适用于治疗广泛的单基因疾病。
