将腺相关病毒（AAV）载体递送至 Superior橄榄复合体可通过轴突运输实现高效的成人耳蜗转导。

Delivery of AAV vectors to the superior olivary complex enables efficient adult cochlear transduction via axonal transport.

作者信息

Naidoo Jerusha, Ren Yin, Rocco Matthew, Bielefeld Eric, O'Brien Allison, Kuo Hsuan-Chih, McFarland Nathan, Avenarius Matthew, Takhar Manpreet, Frank Geneva, Van Laar Victor, Bankiewicz Krystof

机构信息

Department of Neurological Surgery, Gene Therapy Institute, The Ohio State University, 2255 Kenny Road, Columbus, OH 43210, USA.

Department of Otolaryngology- Head and Neck Surgery, The Ohio State University, 915 Olentangy River Road, Columbus, OH 43212, USA.

出版信息

Mol Ther. 2025 May 28. doi: 10.1016/j.ymthe.2025.05.022.

DOI:10.1016/j.ymthe.2025.05.022

PMID:40443032

Abstract

Significant breakthroughs have been made in translation of adeno-associated virus (AAV) vectors for hearing disorders targeting auditory hair cells (HCs). In addition to HCs, spiral ganglion neurons (SGNs) are also impacted in a large number of sensorineural hearing loss cases in adults. However when administered directly into the cochlea in rodents aged older than P1-P3, AAV-mediated SGN transduction efficiency decreases dramatically. An efficient gene-delivery method to transduce adult SGNs is needed. Our group has a track record of utilizing axonal transport to transduce brain structures distal from the site of AAV injection. We investigated whether SGNs could be transduced in adult rats following intraparenchymal AAV administration to the olivary complex. Cochlear transduction was observed with the following common AAV serotypes expressing green fluorescent protein: AAV6, AAV9, AAV-Anc80, and AAV-PhP.B. Cochlear transduction was observed with all serotypes, but the cellular tropism and efficiency of gene transfer varied across the cochlear spiral (apex, middle, base) with different AAV serotypes, with some transducing both SGNs and HCs, while others transduced SGNs or HCs exclusively. This study provides proof of concept that AAV delivery to the olivary complex can efficiently deliver transgenes to SGNs in the adult mammalian cochlea.

摘要

在针对听觉毛细胞（HCs）的听力障碍腺相关病毒（AAV）载体翻译方面已取得重大突破。除了毛细胞外，螺旋神经节神经元（SGNs）在大量成人感音神经性听力损失病例中也受到影响。然而，当在大于P1 - P3的啮齿动物中直接注入耳蜗时，AAV介导的SGN转导效率会急剧下降。因此需要一种有效的基因递送方法来转导成年SGNs。我们团队有利用轴突运输来转导远离AAV注射部位的脑结构的记录。我们研究了在向橄榄复合体实质内注射AAV后，成年大鼠的SGNs是否能被转导。使用以下表达绿色荧光蛋白的常见AAV血清型观察到了耳蜗转导：AAV6、AAV9、AAV - Anc80和AAV - PhP.B。所有血清型均观察到耳蜗转导，但不同AAV血清型在耳蜗螺旋（顶端、中部、基部）的细胞嗜性和基因转移效率有所不同，有些转导SGNs和HCs，而另一些则仅转导SGNs或HCs。本研究提供了概念验证，即向橄榄复合体递送AAV可以有效地将转基因递送至成年哺乳动物耳蜗中的SGNs。