Comparison of high-dose intracisterna magna and lumbar puncture intrathecal delivery of AAV9 in mice to treat neuropathies.
Comparison of high-dose intracisterna magna and lumbar puncture intrathecal delivery of AAV9 in mice to treat neuropathies.
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DOI：
10.1016/j.brainres.2020.146832
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发表时间：
2020-07-15
期刊：
影响因子：
2.9
通讯作者：
Gray SJ
中科院分区：
文献类型：
--
作者：
Bailey RM;Rozenberg A;Gray SJ
神经系统疾病的基因治疗临床试验正在进行中，使用鞘内注射腺相关病毒（AAV）载体直接进入脑脊液。这些试验的初步结果和广泛动物研究的结果提供了令人信服的数据，支持鞘内给药AAV载体治疗遗传性神经疾病的安全性和益处。鞘内分娩可以通过腰椎穿刺（LP）或大脑膜内注射（ICM）来实现，尽管由于手术风险增加，ICM在临床实践中不常用。很少有研究直接比较这些传递方式，关于PNS转导的报道也很有限。为了进一步测试ICM或LP传递对神经病变的效用，我们对小鼠大池或腰椎蛛网膜下腔注射表达GFP的AAV血清型9 （AAV9）载体进行了头对头的比较。我们报道了AAV9在小鼠鞘内的基因传递导致大脑和脊髓中神经元和胶质细胞的稳定转导，并且具有广泛的分布，包括PNS的成分。ICM注射后，载体在脑和PNS区域的表达量明显增加，而LP注射后，下脊髓和周围器官的载体表达量明显增加。这些发现支持鞘内AAV9给药是遗传性神经病变的一种翻译相关的给药方法。
Gene therapy clinical trials for neurological disorders are ongoing using intrathecal injection of adeno-associated virus (AAV) vector directly into the cerebral spinal fluid. Preliminary findings from these trials and results from extensive animal studies provides compelling data supporting the safety and benefit of intrathecal delivery of AAV vectors for inherited neurological disorders. Intrathecal delivery can be achieved by a lumbar puncture (LP) or intracisterna magna (ICM) injection, although ICM is not commonly used in clinical practice due to increased procedural risk. Few studies directly compared these delivery methods and there are limited reports on transduction of the PNS. To further test the utility of ICM or LP delivery for neuropathies, we performed a head to head comparison of AAV serotype 9 (AAV9) vectors expressing GFP injected into the cisterna magna or lumbar subarachnoid space in mice. We report that an intrathecal gene delivery of AAV9 in mice leads to stable transduction of neurons and glia in the brain and spinal cord and has a widespread distribution that includes components of the PNS. Vector expression was notably higher in select brain and PNS regions following ICM injection, while higher amounts of vector was found in the lower spinal cord and peripheral organs following LP injection. These findings support that intrathecal AAV9 delivery is a translationally relevant delivery method for inherited neuropathies.
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影响因子：
12.4
作者：
Duque, Sandra;Joussemet, Beatrice;Barkats, Martine
通讯作者：
Barkats, Martine
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
DOI：
10.1038/mtm.2014.51
发表时间：
2014
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.4
作者：
Samaranch, Lluis;Sebastian, Waldy San;Bankiewicz, Krystof S.
通讯作者：
Bankiewicz, Krystof S.
影响因子：
5.1
作者：
McCarty, DM;Fu, H;Samulski, RJ
通讯作者：
Samulski, RJ