Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system
Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system
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DOI：
10.1096/fj.11-182311
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Waddington, Simon N.
中科院分区：
文献类型：
--
作者：
Rahim, Ahad A.;Wong, Andrew M. S.;Waddington, Simon N.
几种神经系统疾病的特征是神经变性和儿童期死亡。常规药物是无效的，但胎儿或新生儿基因治疗可能提供一种替代治疗途径。我们评估了单链和自身互补的腺相关病毒假型2/9（AAV 2/9）的能力，使神经系统和靶基因表达特定的神经细胞类型静脉注射到胎儿和新生小鼠，使用对照未注射的年龄匹配的小鼠。胎仔和新生儿给药产生了对中枢（脑、脊髓和视网膜的所有层）和外周（肌间神经丛和支配神经）神经系统的全面递送，但在脑内具有不同的表达谱;胎仔和新生儿给药分别导致神经元和原生质星形胶质细胞中的表达。无论是单链还是自身互补的AAV 2/9在任一施用后都没有触发小胶质细胞介导的免疫应答。总之，静脉内AAV 2/9将基因表达靶向于依赖于发育阶段的特定神经细胞类型。这是研究神经系统发育和疾病的有力工具。此外，它可以提供一种治疗策略，用于治疗早期致命的遗传疾病，如戈谢病，以及致残性神经病，如早产儿脑损伤。Rahim，A.一、黄氏A. M.美国，Hoefer，K.，巴克利，S。M. K.，马塔尔角N.，Cheng，S. H、Chan，J. K.是的，库珀，J. D.，Waddington，S. N.将AAV 2/9静脉内施用至胎儿和新生小鼠导致中枢神经系统细胞类型的差异靶向和神经系统的广泛转导。FASEB J.25，3505-3518（2011）。www.fasebj.org
Several diseases of the nervous system are characterized by neurodegeneration and death in childhood. Conventional medicine is ineffective, but fetal or neonatal gene therapy may provide an alternative route to treatment. We evaluated the ability of single-stranded and self-complementary adeno-associated virus pseudotype 2/9 (AAV2/9) to transduce the nervous system and target gene expression to specific neural cell types following intravenous injection into fetal and neonatal mice, using control uninjected age-matched mice. Fetal and neonatal administration produced global delivery to the central (brain, spinal cord, and all layers of the retina) and peripheral (myenteric plexus and innervating nerves) nervous system but with different expression profiles within the brain; fetal and neonatal administration resulted in expression in neurons and protoplasmic astrocytes, respectively. Neither single-stranded nor self-complementary AAV2/9 triggered a microglia-mediated immune response following either administration. In summary, intravenous AAV2/9 targets gene expression to specific neural cell types dependent on developmental stage. This represents a powerful tool for studying nervous system development and disease. Furthermore, it may provide a therapeutic strategy for treatment of early lethal genetic diseases, such as Gaucher disease, and for disabling neuropathies, such as preterm brain injury.-Rahim, A. A., Wong, A. M. S., Hoefer, K., Buckley, S. M. K., Mattar, C. N., Cheng, S. H., Chan, J. K. Y., Cooper, J. D., Waddington, S. N. Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of central nervous system cell types and extensive transduction of the nervous system. FASEB J. 25, 3505-3518 (2011). www.fasebj.org