Recent studies have demonstrated that delivery of genes to the inner ear can achieve a variety of effects ranging from support of auditory neuron survival to protection and restoration of hair cells, demonstrating the utility of vector based gene delivery. Translation of these findings to useful experimental systems or even clinical applications requires a detailed understanding of the pharmacokinetics of gene delivery in the inner ear. Ideal gene delivery systems will employ a well tolerated vector which efficiently transduces the appropriate target cells within a tissue, but spare non-target structures. Adenovectors based on serotype 5 (Ad 5) are commonly used vectors, are easy to construct and have a long track record of efficacious gene transfer in the inner ear. In this study we demonstrate that distribution of Ad5 vector occurs in a basal to apical gradient with rapid distribution of vector to the vestibule after delivery via a round window cochleostomy. Transduction of the vector and expression of the delivered transgene occurs by 10 min post vector delivery. At 24 h post delivery only 16% of vector that was initially detectable within the inner ear by quantitative PCR remained. Perilymph sampling was used to determine that vector concentrations in perilymph peaked at 30 min post delivery and then declined rapidly. Understanding these basic distribution patterns and parameters for delivery are important for the design of gene delivery vectors and vital for modeling dose responses to achieve safe efficacious delivery of a therapeutic agent.

译文

最近的研究表明,将基因递送到内耳可以实现多种效果,从支持听觉神经元存活到保护和恢复毛细胞,证明了基于载体的基因递送的实用性。将这些发现转化为有用的实验系统甚至临床应用,需要对内耳基因传递的药代动力学有详细的了解。理想的基因递送系统将采用耐受性良好的载体,该载体可以有效地转导组织内的适当靶细胞,但保留非靶标结构。基于血清型5 (Ad 5) 的腺载体是常用的载体,易于构建,并且在内耳中有效基因转移的记录很长。在这项研究中,我们证明了Ad5载体的分布发生在基础到顶端的梯度中,并且通过圆窗耳蜗造口术将载体快速分布到前庭。载体的转导和递送的转基因的表达发生在载体递送后10分钟。在递送后24小时,仅保留通过定量PCR在内耳内最初可检测到的载体的16%。外淋巴采样用于确定外淋巴中的载体浓度在分娩后30分钟达到峰值,然后迅速下降。了解这些基本的分布模式和递送参数对于基因递送载体的设计很重要,并且对于模拟剂量反应以实现治疗剂的安全有效递送至关重要。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录