Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.
Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.
复制标题
内部对流增强了靶向主要感觉神经元的AAVRH20的递送。
DOI：
10.1016/j.mcn.2014.04.004
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Beutler AS
中科院分区：
文献类型：
--
作者：
Pleticha J;Jeng-Singh C;Rezek R;Zaibak M;Beutler AS
使用腺相关病毒（AAV）的基因治疗是治疗周围神经系统（PNS）疾病（例如慢性疼痛或周围神经病变）的有吸引力的策略。尽管AAV的鞘内（IT）施用已经是靶向PNS的领域中的标准，但是其缺乏解剖学特异性并且导致载体的宽的喙尾分布。另一种方法是将AAV直接递送至外周神经轴突。本研究采用对流增强递送（CED）将表达增强型绿色荧光蛋白（EGFP）的新型AAV血清型AAVrh20递送到大鼠坐骨神经中，研究其与IT途径相比的功效、解剖学选择性和安全性。神经内CED导致转导局限于同侧L4和L5 DRG，而IT给药导致混杂DRG转导，双侧涵盖整个腰椎区域。神经内AAV施用的转导率与IT递送相似（L4 DRG为24%，L5 DRG为31.5%，而L4 DRG为50%，L5 DRG为19.5%）。使用高渗稀释液不能进一步提高转导效率。AAVrh20上级于先前描述的对每种途径最具活性的参考血清型。AAV的神经内CED与自发消退的一过性异常性疼痛相关。这些发现确立了神经内CED作为IT给药的替代方案，用于AAV介导的基因转移至PNS，并且基于参考啮齿动物模型，表明AAVrh20作为靶向PNS的上级血清型。
Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). Use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS.
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DOI：
10.1038/mt.2008.166
发表时间：
2008-10
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.jvir.2010.02.027
发表时间：
2010-08-01
影响因子：
2.9
作者：
French, J. Tyler;Goins, Beth;Bao, Ande
通讯作者：
Bao, Ande
影响因子：
56.9
作者：
Kaspar, BK;Lladó, J;Gage, FH
通讯作者：
Gage, FH
影响因子：
15.9
作者：
Ashtari, Manzar;Cyckowski, Laura L.;Bennett, Jean
通讯作者：
Bennett, Jean
影响因子：
12.4
作者：
Lawlor, Patricia A.;Bland, Ross J.;During, Matthew J.
通讯作者：
During, Matthew J.