Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparan and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodegeneration, intellectual disability, and death by age 10. Current treatments for this disease include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, these treatments do not address CNS manifestations of the disease. In this study we compared the ability of intravenously administered AAV serotypes 9 and rh10 (AAV9 and AAVrh10) for delivery and expression of the IDUA gene in the CNS. Adult C57BL/6 MPS I mice were infused intravenously with either AAV9 or AAVrh10 vector encoding the human IDUA gene. Treated animals demonstrated supraphysiological levels and widespread restoration of IDUA enzyme activity in the plasma and all organs including the CNS. High levels of IDUA enzyme activity were observed in the plasma, brain and spinal cord ranging from 10 to 100-fold higher than heterozygote controls, while levels in peripheral organs were also high, ranging from 1000 to 10,000-fold higher than control animals. In general, levels of IDUA expression were slightly higher in peripheral organs for AAVrh10 administered animals although these differences were not significant except for the lung. Levels of IDUA expression between AAV 9 and rh10 were roughly equivalent in the brain. Urinary and tissue GAGs were significantly reduced starting at 3 weeks after vector infusion, with restoration of normal GAG levels by the end of the study in animals treated with either AAV9 or rh10. These results demonstrate that non-invasive intravenous AAV9 or AAVrh10-mediated IDUA gene therapy is a potentially effective treatment for both systemic and CNS manifestations of MPS I, with implications for the treatment of other metabolic and neurological diseases as well.

I 型粘多糖贮积症 (MPS I) 是一种遗传性代谢性疾病，由 α-L-艾杜糖醛酸酶 (IDUA) 缺乏引起，导致乙酰肝素和硫酸皮肤素糖胺聚糖 (GAG) 积累。患有最严重疾病（Hurler 综合征）的个体会在 10 岁时出现神经退行性疾病、智力障碍和死亡。目前治疗这种疾病的方法包括同种异体造血干细胞移植 (HSCT) 和酶替代疗法 (ERT)。然而，这些治疗并不能解决该疾病的中枢神经系统表现。在这项研究中，我们比较了静脉注射 AAV 血清型 9 和 rh10（AAV9 和 AAVrh10）在中枢神经系统中递送和表达 IDUA 基因的能力。成年 C57BL/6 MPS I 小鼠静脉注射编码人 IDUA 基因的 AAV9 或 AAVrh10 载体。接受治疗的动物在血浆和包括中枢神经系统在内的所有器官中表现出超生理水平和 IDUA 酶活性的广泛恢复。在血浆、大脑和脊髓中观察到高水平的 IDUA 酶活性，比杂合子对照高 10 至 100 倍，而外周器官的水平也很高，比对照动物高 1000 至 10,000 倍。一般而言，给予 AAVrh10 的动物的外周器官中 IDUA 表达水平略高，但除肺外这些差异并不显着。 AAV 9 和 rh10 之间的 IDUA 表达水平在大脑中大致相当。从载体输注后 3 周开始，尿液和组织中的 GAG 显着降低，在研究结束时，用 AAV9 或 rh10 治疗的动物恢复正常的 GAG 水平。 这些结果表明，非侵入性静脉注射 AAV9 或 AAVrh10 介导的 IDUA 基因治疗是治疗 MPS I 的全身和 CNS 表现的潜在有效方法，对其他代谢和神经系统疾病的治疗也具有影响。