Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
Intravenous delivery for treatment of mucopolysaccharidosis type I: A comparison of AAV serotypes 9 and rh10
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DOI：
10.1016/j.ymgmr.2020.100604
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发表时间：
2020-09-01
影响因子：
1.9
通讯作者：
McIvor, R. Scott
中科院分区：
文献类型：
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作者：
Belur, Lalitha R.;Podetz-Pedersen, Kelly M.;McIvor, R. Scott
I型粘多糖沉积症（MPS I）是一种由α-L-艾杜糖醛酸酶（IDUA）缺乏引起的遗传性代谢紊乱，导致乙酰肝素和硫酸皮肤素糖胺聚糖（GAG）蓄积。患有最严重形式的疾病（Hurler综合征）的个体患有神经变性，智力残疾，并在10岁时死亡。目前对这种疾病的治疗包括异基因造血干细胞移植（HSCT）和酶替代疗法（ERT）。然而，这些治疗不能解决疾病的CNS表现。在这项研究中，我们比较了静脉内施用的AAV血清型9和rh 10（AAV 9和AAVrh 10）在CNS中递送和表达IDUA基因的能力。将成年C57 BL/6 MPS I小鼠静脉内输注编码人IDUA基因的AAV 9或AAVrhlO载体。给药动物的血浆和所有器官（包括CNS）中的IDUA酶活性显示出超生理水平和广泛恢复。在血浆、脑和脊髓中观察到高水平的IDUA酶活性，范围为杂合子对照的10至100倍，而外周器官中的水平也很高，范围为对照动物的1000至10，000倍。一般而言，施用AAVrh 10的动物的外周器官中IDUA表达水平略高，尽管这些差异除肺外不显著。AAV 9和rh 10之间的IDUA表达水平在脑中大致相等。在载体输注后3周开始，尿和组织GAG显著降低，在用AAV 9或rh 10处理的动物中，到研究结束时恢复正常GAG水平。这些结果表明，非侵入性静脉内AAV 9或AAVrh 10介导的IDUA基因治疗是MPS I的全身和CNS表现的潜在有效治疗，也适用于其他代谢和神经系统疾病的治疗。
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.