University of the Witwatersrand, School of Pathology, Antiviral Gene Therapy Research Unit, Health Sciences Faculty, Private Bag 3, WITS 2050, South Africa.
Expert Opin Drug Deliv. 2010 Dec;7(12):1373-85. doi: 10.1517/17425247.2010.533655. Epub 2010 Nov 13.
Harnessing RNA interference (RNAi) to silence pathology-causing genes has shown promise as a mode of therapy. The sustained gene inhibition that may be achieved with expressed sequences is potentially useful for treatment of chronic viral infections, but efficient and safe delivery of these sequences remains a challenge. It is generally recognized that there is no ideal vector for all therapeutic RNAi applications, but recombinant adenovirus vectors are well suited to hepatic delivery of expressed RNAi activators.
Adenoviruses are hepatotropic after systemic administration, and this is useful for delivering expressed RNAi activators that silence pathology-causing genes in the liver. However, drawbacks of adenoviruses are toxicity and diminished efficacy, which result from induction of innate and adaptive immune responses. In this review, the advantages and hurdles facing therapeutic application of adenoviral vectors for liver delivery of RNAi effectors are covered.
Insights into adenovirus vectorology and the methods that have been used to make these vectors safer for advancing clinical application of RNAi-based therapy.
Adenoviruses are very powerful hepatotropic vectors. To make adenoviruses more effective for clinical use, polymer conjugation and deletion of viral vector sequences have been used successfully. However, further modifications to attenuate immunostimulation as well as improvements in large-scale production are necessary before the therapeutic potential of adenovirus-mediated delivery of RNAi activators is realized.
利用 RNA 干扰 (RNAi) 沉默致病基因已显示出作为一种治疗模式的潜力。通过表达序列实现的持续基因抑制对于治疗慢性病毒感染可能是有用的，但这些序列的有效和安全传递仍然是一个挑战。人们普遍认识到，没有一种理想的载体适用于所有治疗性 RNAi 应用，但重组腺病毒载体非常适合肝脏表达 RNAi 激活剂的递送。
全身性给药后，腺病毒具有嗜肝性，这对于递呈表达 RNAi 激活剂以沉默肝脏中的致病基因很有用。然而，腺病毒的毒性和功效降低的缺点是由先天和适应性免疫反应引起的。在这篇综述中，涵盖了治疗性应用腺病毒载体进行肝脏 RNAi 效应器递呈所面临的优势和障碍。
深入了解腺病毒载体学以及用于使这些载体更安全地推进基于 RNAi 的治疗临床应用的方法。
腺病毒是非常强大的嗜肝性载体。为了使腺病毒在临床应用中更有效，已经成功地使用聚合物缀合和病毒载体序列缺失。然而，在实现腺病毒介导的 RNAi 激活剂递送的治疗潜力之前，还需要进一步修饰以减轻免疫刺激以及改进大规模生产。
