Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle
Efficient Retrograde Transport of Adeno-Associated Virus Type 8 to Spinal Cord and Dorsal Root Ganglion After Vector Delivery in Muscle
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DOI：
10.1089/hum.2009.131
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发表时间：
2010-01-01
影响因子：
4.2
通讯作者：
Xiao, Xiao
中科院分区：
文献类型：
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作者：
Zheng, Hui;Qiao, Chunping;Xiao, Xiao
周围神经系统（PNS），包括周围神经和背根神经节（DRG），涉及许多神经障碍，例如周围神经病（糖尿病性神经病、慢性疼痛等）。和脱髓鞘疾病（多发性硬化、先天性肌营养不良、腓骨肌萎缩症等）。针对这些疾病的有效临床干预措施非常有限。基因治疗是治疗PNS疾病的一种新的策略，尤其是具有简单和微创的递送方法。以前，我们已经证明，腺相关病毒8型（AAV 8）可以有效地通过简单的腹腔注射新生小鼠全身肌肉。在这项研究中，我们研究了AAV 8在新生小鼠中通过腹腔注射转导PNS的能力，以及在成年小鼠中通过肌肉注射转导PNS的能力。有效和长期的基因转移被发现在白色物质的脊髓，背根神经节神经元，周围神经在两组，无论是作为新生儿或成人，特别是新生儿。在一条后腿的胫骨前肌和腓肠肌中注射AAV 8的成年小鼠中，脊髓下部比上部转导更多的神经元; DRG神经元在载体注射侧比对侧未注射侧转导更多。无论小鼠的传递方法和年龄如何，脊髓灰质中的少数细胞被转导。这些结果支持载体逆行转运的机制，并表明AAV 8穿过血-神经屏障的能力较差。我们的发现对周围神经系统疾病的基因治疗具有重要意义。
The peripheral nervous system (PNS), including peripheral nerves and dorsal root ganglion (DRG), is involved in numerous neurological disorders, such as peripheral neuropathies (diabetic neuropathy, chronic pain, etc.) and demyelination diseases (multiple sclerosis, congenital muscular dystrophy, Charcot-Marie-Tooth disease, etc.). Effective clinical interventions for those diseases are very limited. Gene therapy represents a novel therapeutic strategy for the PNS diseases, especially with simply and minimally invasive delivery methods. Previously, we have shown that adeno-associated virus type 8 (AAV8) can efficiently transduce muscles body wide by a simple intraperitoneal injection in neonatal mice. In this study, we investigated the capacity of AAV8 in transducing PNS in neonatal mice by intraperitoneal injection and also in adult mice by intramuscular injection. Efficient and long-term gene transfer was found in the white matter of the spinal cord, DRG neurons, and peripheral nerves in both groups, treated either as neonates or as adults, particularly neonates. In the adult mice injected with AAV8 in tibialis anterior and gastrocnemius muscles in one of the hind legs, more neurons were transduced in the lower part of the spinal cord than in the upper part; the DRG neurons were transduced more on the vector-injected side than in the contralateral uninjected side. Few cells in the gray matter of the spinal cord were transduced regardless of the delivery methods and age of the mice. These results support the mechanism of vector retrograde transport and suggest that AAV8 crosses blood-nerve barrier poorly. Our finding should have important implications in gene therapy for peripheral neurological disorders.