Comparative Effectiveness of Intracerebroventricular, Intrathecal, and Intranasal Routes of AAV9 Vector Administration for Genetic Therapy of Neurologic Disease in Murine Mucopolysaccharidosis Type I.
Comparative Effectiveness of Intracerebroventricular, Intrathecal, and Intranasal Routes of AAV9 Vector Administration for Genetic Therapy of Neurologic Disease in Murine Mucopolysaccharidosis Type I.
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DOI：
10.3389/fnmol.2021.618360
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发表时间：
2021
影响因子：
4.8
通讯作者：
McIvor RS
中科院分区：
文献类型：
--
作者：
Belur LR;Romero M;Lee J;Podetz-Pedersen KM;Nan Z;Riedl MS;Vulchanova L;Kitto KF;Fairbanks CA;Kozarsky KF;Orchard PJ;Frey WH 2nd;Low WC;McIvor RS
I型粘多糖样变性（MPS I）是一种由溶酶体酶α-L-艾杜糖醛酸酶（IDUA）缺乏引起的遗传性代谢紊乱。目前的两种治疗方法[造血干细胞移植（HSCT）和酶替代疗法（ERT）]在解决神经系统疾病方面不够有效，部分原因是溶酶体酶无法穿过血脑屏障。为了更有效地治疗神经系统疾病，我们研究了使用几种不同的给药途径将AAV介导的IDUA基因递送至大脑的有效性。通过直接脑室内（ICV）注射、通过鞘内（IT）输注到脑脊液中或通过鼻内（IN）滴注AAV 9-IDUA载体来处理动物。将AAV 9-IDUA施用于用环磷酰胺（CP）免疫抑制或在出生时通过每周注射人艾杜糖醛酸酶免疫耐受的IDUA缺陷小鼠。在通过ICV或IT给药处理的动物中，IDUA酶的水平范围为显微解剖脑的所有部分中野生型水平的3至1000倍。在鼻内给予载体的动物中，嗅球中的酶水平是野生型的100倍，但大脑其他部位的酶表达接近野生型水平。在ICV和IT处理的小鼠中，糖胺聚糖水平降低至正常，并且在IN处理的小鼠中，它们在嗅球中正常化，或在脑的其他部分中降低。免疫组织化学分析显示，在ICV处理的小鼠的大脑的所有部分中广泛的IDUA表达，而IT处理的动物显示主要限于后脑的转导，在中脑和前脑中观察到一些零星的标记。在6月龄时，在巴恩斯迷宫中测试动物的空间导航、记忆和神经认知功能;所有治疗的动物与正常杂合对照动物无法区分，而未治疗的IDUA缺陷动物表现出显著的学习和空间导航缺陷。我们得出结论，IT和IN途径分别是AAV载体递送至具有有效IDUA表达的脑的可接受的和替代的给药途径，而所有三种给药途径防止小鼠MPS I模型中神经认知缺陷的出现。
Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). The two current treatments [hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT)], are insufficiently effective in addressing neurologic disease, in part due to the inability of lysosomal enzyme to cross the blood brain barrier. With a goal to more effectively treat neurologic disease, we have investigated the effectiveness of AAV-mediated IDUA gene delivery to the brain using several different routes of administration. Animals were treated by either direct intracerebroventricular (ICV) injection, by intrathecal (IT) infusion into the cerebrospinal fluid, or by intranasal (IN) instillation of AAV9-IDUA vector. AAV9-IDUA was administered to IDUA-deficient mice that were either immunosuppressed with cyclophosphamide (CP), or immunotolerized at birth by weekly injections of human iduronidase. In animals treated by ICV or IT administration, levels of IDUA enzyme ranged from 3- to 1000-fold that of wild type levels in all parts of the microdissected brain. In animals administered vector intranasally, enzyme levels were 100-fold that of wild type in the olfactory bulb, but enzyme expression was close to wild type levels in other parts of the brain. Glycosaminoglycan levels were reduced to normal in ICV and IT treated mice, and in IN treated mice they were normalized in the olfactory bulb, or reduced in other parts of the brain. Immunohistochemical analysis showed extensive IDUA expression in all parts of the brain of ICV treated mice, while IT treated animals showed transduction that was primarily restricted to the hind brain with some sporadic labeling seen in the mid- and fore brain. At 6 months of age, animals were tested for spatial navigation, memory, and neurocognitive function in the Barnes maze; all treated animals were indistinguishable from normal heterozygous control animals, while untreated IDUA deficient animals exhibited significant learning and spatial navigation deficits. We conclude that IT and IN routes are acceptable and alternate routes of administration, respectively, of AAV vector delivery to the brain with effective IDUA expression, while all three routes of administration prevent the emergence of neurocognitive deficiency in a mouse MPS I model.
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影响因子：
12.4
作者：
Duque, Sandra;Joussemet, Beatrice;Barkats, Martine
通讯作者：
Barkats, Martine
影响因子：
1.9
作者：
Belur, Lalitha R.;Podetz-Pedersen, Kelly M.;McIvor, R. Scott
通讯作者：
McIvor, R. Scott
毒理学研究在恒河猕猴中表达人α-l-二维罗酮酶的甲状腺内腺体腺相关病毒9。
DOI：
10.1016/j.omtm.2018.06.003
发表时间：
2018-09-21
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Hordeaux J;Hinderer C;Goode T;Katz N;Buza EL;Bell P;Calcedo R;Richman LK;Wilson JM
通讯作者：
Wilson JM
影响因子：
3.5
作者：
Aronovich, Elena L.;Bell, Jason B.;Hackett, Perry B.
通讯作者：
Hackett, Perry B.
影响因子：
4.2
作者：
Belur, Lalitha R.;Temme, Alexa;McIvor, R. Scott
通讯作者：
McIvor, R. Scott