Toxicology Study of Intra-Cisterna Magna Adeno-Associated Virus 9 Expressing Human Alpha-L-Iduronidase in Rhesus Macaques.
Toxicology Study of Intra-Cisterna Magna Adeno-Associated Virus 9 Expressing Human Alpha-L-Iduronidase in Rhesus Macaques.
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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
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发表时间：
2018-09-21
期刊：
影响因子：
--
通讯作者：
Wilson JM
中科院分区：
文献类型：
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作者：
Hordeaux J;Hinderer C;Goode T;Katz N;Buza EL;Bell P;Calcedo R;Richman LK;Wilson JM
I型粘多糖样变性是一种由溶酶体酶α-L-艾杜糖醛酸酶缺乏引起的隐性遗传疾病，其导致最严重形式的神经退行性和全身性疾病，称为Hurler综合征。几项临床试验正在评估腺相关病毒血清型9（AAV 9）用于治疗神经退行性疾病。尽管这些试验集中于全身或腰椎给药，但通过枕下穿刺至枕大池的鞘内给药在大型动物中显示出显著的疗效。因此，我们进行了符合药物非临床研究质量管理规范的非临床研究，以研究人α-L-艾杜糖醛酸酶的枕下AAV 9基因转移至非人灵长类动物的安全性。我们给22只恒河猴（包括3只免疫抑制动物）注射了载体或两种载体剂量中的一种。我们评估了活体安全性和免疫反应。在载体给药后14、90或180天对动物实施安乐死，并评价组织病理学和生物分布。未发生手术相关病变或不良事件。所有载体处理的动物在脑脊液中显示出剂量依赖性单核细胞增多，背根神经节神经元和相关轴突的轻微至中度无症状变性。这些研究支持枕下AAV递送治疗Hurler综合征的临床开发，并强调了潜在的感觉神经元毒性，需要在首次人体研究中仔细监测。
Mucopolysaccharidosis type I is a recessive genetic disease caused by deficiency of the lysosomal enzyme α-L-iduronidase, which leads to a neurodegenerative and systemic disease called Hurler syndrome in its most severe form. Several clinical trials are evaluating adeno-associated virus serotype 9 (AAV9) for the treatment of neurodegenerative diseases. Although these trials focus on systemic or lumbar administration, intrathecal administration via suboccipital puncture into the cisterna magna has demonstrated remarkable efficacy in large animals. We, therefore, conducted a good laboratory practice-compliant non-clinical study to investigate the safety of suboccipital AAV9 gene transfer of human α-L-iduronidase into nonhuman primates. We dosed 22 rhesus macaques, including three immunosuppressed animals, with vehicle or one of two doses of vector. We assessed in-life safety and immune responses. Animals were euthanized 14, 90, or 180 days post-vector administration and evaluated for histopathology and biodistribution. No procedure-related lesions or adverse events occurred. All vector-treated animals showed a dose-dependent mononuclear pleocytosis in the cerebrospinal fluid and minimal to moderate asymptomatic degeneration of dorsal root ganglia neurons and associated axons. These studies support the clinical development of suboccipital AAV delivery for Hurler syndrome and highlight a potential sensory neuron toxicity that warrants careful monitoring in first-in-human studies.
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DOI：
10.1038/mtm.2014.51
发表时间：
2014
期刊：
Molecular therapy. Methods & clinical development
影响因子：
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作者：
通讯作者：
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作者：
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Wilson, James M.
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DOI：
10.1038/mt.2011.157
发表时间：
2011-11
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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