Incisionless targeted adeno-associated viral vector delivery to the brain by focused ultrasound-mediated intranasal administration.
Incisionless targeted adeno-associated viral vector delivery to the brain by focused ultrasound-mediated intranasal administration.
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DOI：
10.1016/j.ebiom.2022.104277
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发表时间：
2022-10
期刊：
影响因子：
11.1
通讯作者：
Chen, Hong
中科院分区：
文献类型：
--
作者：
Ye, Dezhuang;Yuan, Jinyun;Yang, Yaoheng;Yue, Yimei;Hu, Zhongtao;Fadera, Siaka;Chen, Hong
关键词：
腺相关病毒（AAV）载体目前是基因治疗的主要平台，具有治疗多种中枢神经系统（CNS）疾病的潜力。将aav输送到中枢神经系统的方法有很多，如直接颅内注射（DI）、鼻内给药（IN）和静脉注射（聚焦超声诱导血脑屏障破坏（FUS-BBBD））。然而，如何以最小的系统毒性将aav无创、高效地输送到大脑仍然是主要的挑战。本研究旨在探讨聚焦超声介导的鼻内给药（FUSIN）在AAV脑内给药中的潜力。小鼠鼻内注射编码增强绿色荧光蛋白（AAV5- egfp）的AAV5，然后在全身注射微泡的情况下进行FUS超声。采集小鼠脑和其他主要器官进行免疫组织染色、PCR定量和原位杂交。比较AAV与DI、FUS-BBBD和IN的交付结果。FUSIN实现了AAV5-EGFP安全有效地递送到空间目标脑位置，包括脑浅表部位（皮层）和脑深部区域（脑干）。FUSIN与已建立的DI的递送效果相当，其递送效率比FUS-BBBD和IN分别高出414.9倍和2073.7倍。FUSIN在外周器官的生物分布最小，与DI相当。我们的研究结果表明，FUSIN是一种有前途的无创、高效、安全、空间靶向的AAV脑递送技术。美国国立卫生研究院（NIH）资助R01EB027223， R01EB030102， R01MH116981和UG3MH126861。
Adeno-associated viral (AAV) vectors are currently the leading platform for gene therapy with the potential to treat a variety of central nervous system (CNS) diseases. There are numerous methods for delivering AAVs to the CNS, such as direct intracranial injection (DI), intranasal delivery (IN), and intravenous injection with focused ultrasound-induced blood–brain barrier disruption (FUS-BBBD). However, non-invasive and efficient delivery of AAVs to the brain with minimal systemic toxicity remain the major challenge. This study aims to investigate the potential of focused ultrasound-mediated intranasal delivery (FUSIN) in AAV delivery to brain. Mice were intranasally administered with AAV5 encoding enhanced green fluorescence protein (AAV5-EGFP) followed by FUS sonication in the presence of systemically injected microbubbles. Mouse brains and other major organs were harvested for immunohistological staining, PCR quantification, and in situ hybridization. The AAV delivery outcomes were compared with those of DI, FUS-BBBD, and IN delivery. FUSIN achieved safe and efficient delivery of AAV5-EGFP to spatially targeted brain locations, including a superficial brain site (cortex) and a deep brain region (brainstem). FUSIN achieved comparable delivery outcomes as the established DI, and displayed 414.9-fold and 2073.7-fold higher delivery efficiency than FUS-BBBD and IN. FUSIN was associated with minimal biodistribution in peripheral organs, which was comparable to that of DI. Our results suggest that FUSIN is a promising technique for non-invasive, efficient, safe, and spatially targeted AAV delivery to the brain. National Institutes of Health (NIH) grants R01EB027223, R01EB030102, R01MH116981, and UG3MH126861.
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