Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs
Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs
复制标题
DOI：
10.1016/j.ymthe.2018.03.004
复制
发表时间：
2018-05-02
影响因子：
12.4
通讯作者：
Kopke, Richard D.
中科院分区：
文献类型：
--
作者：
Du, Xiaoping;Cai, Qunfeng;Kopke, Richard D.
耳聋通常是由哺乳动物耳蜗毛细胞（HC）由于噪声创伤，毒素或感染而造成的不可逆损失引起的。我们以前证明，针对Notch途径基因的小干扰RNA（siRNA），多毛和分裂增强子1（Hes 1），封装在生物相容性聚（乳酸-羟基乙酸）纳米颗粒（PLGA NPs）可以再生耳毒素消融小鼠器官型培养物内的HC。在本研究中，我们将Hes 1 siRNA（siHes 1）的缓释制剂递送到噪声损伤的成年豚鼠的耳蜗中。在九周的随访期内，通过系列听觉脑干反应测量听觉功能恢复，并通过免疫组织学评估和扫描电子显微镜评估HC再生。在用siHes 1 NP治疗的耳朵中，在宽的音调分布范围内观察到显著的HC恢复和听力恢复，从治疗后三周开始并延伸至治疗后九周。此外，异位和不成熟的HC都是唯一观察到噪音损伤耳蜗siHes 1纳米颗粒治疗，符合从头HC生产。我们的研究结果表明，持久的耳蜗毛细胞再生和促进显着的听力恢复，在成年豚鼠通过可逆调制Hes 1的表达。因此，PLGA-NP介导的siHes 1到耳蜗的传递代表了一种有前途的药理学方法，以在体内再生功能和可持续的哺乳动物HC。
Deafness is commonly caused by the irreversible loss of mammalian cochlear hair cells (HCs) due to noise trauma, toxins, or infections. We previously demonstrated that small interfering RNAs (siRNAs) directed against the Notch pathway gene, hairy and enhancer of split 1 (Hes1), encapsulated within biocompatible poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) could regenerate HCs within ototoxin-ablated murine organotypic cultures. In the present study, we delivered this sustained-release formulation of Hes1 siRNA (siHes1) into the cochleae of noise-injured adult guinea pigs. Auditory functional recovery was measured by serial auditory brainstem responses over a nine-week follow-up period, and HC regeneration was evaluated by immunohistological evaluations and scanning electron microscopy. Significant HC restoration and hearing recovery were observed across a broad tonotopic range in ears treated with siHes1 NPs, beginning at three weeks and extending out to nine weeks post-treatment. Moreover, both ectopic and immature HCs were uniquely observed in noise-injured cochleae treated with siHes1 NPs, consistent with de novo HC production. Our results indicate that durable cochlear HCs were regenerated and promoted significant hearing recovery in adult guinea pigs through reversible modulation of Hes1 expression. Therefore, PLGA-NP-mediated delivery of siHes1 to the cochlea represents a promising pharmacologic approach to regenerate functional and sustainable mammalian HCs in vivo.