Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I
Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I
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DOI：
10.1089/hum.2017.187
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发表时间：
2017-07-01
影响因子：
4.2
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.;Temme, Alexa;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）缺乏引起的进行性、多系统、遗传性代谢疾病。由于溶酶体酶不能穿过血脑屏障，目前对这种疾病的治疗在治疗中枢神经系统（CNS）疾病中无效。通过鼻内施用编码IDUA的腺相关病毒血清型9（AAV 9）载体，在CNS疾病的治疗中采取了非侵入性和有效的方法。用AAV 9-IDUA载体鼻内滴注3月龄的成年IDUA缺陷小鼠。滴注后5个月处死的动物在嗅球中表现出高达野生型小鼠50倍的IDUA酶活性水平，在大脑的所有其他部分恢复了野生型酶水平。用AAV 9-IDUA鼻内处理也导致脑中组织糖胺聚糖储存材料的减少。在鼻上皮和嗅球中观察到组织切片的强IDUA免疫荧光染色，但在脑的其他部分中没有转导细胞存在的证据。这表明，储存物质的减少很可能是由于酶从嗅球和鼻上皮扩散到大脑更深区域的结果。在8月龄时，使用巴恩斯迷宫评估空间导航的神经认知测试表明，治疗的IDUA缺陷小鼠与正常对照动物没有差异，而未治疗的IDUA缺陷小鼠表现出显著的学习和导航缺陷。鼻内AAV 9-IDUA滴注的这种新型非侵入性策略可能用于治疗人MPS I的CNS表现。
Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of alpha-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.