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通过从肝脏特异性启动子表达人工抗乙肝病毒前体微小RNA的辅助依赖型腺病毒载体抑制乙肝病毒复制

Inhibition of hepatitis B virus replication by helper dependent adenoviral vectors expressing artificial anti-HBV pri-miRs from a liver-specific promoter.

作者信息

Mowa Mohube Betty, Crowther Carol, Ely Abdullah, Arbuthnot Patrick

机构信息

Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa.

出版信息

Biomed Res Int. 2014;2014:718743. doi: 10.1155/2014/718743. Epub 2014 Jun 5.

DOI:10.1155/2014/718743
PMID:25003129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4066856/
Abstract

Research on applying RNA interference (RNAi) to counter HBV replication has led to identification of potential therapeutic sequences. However, before clinical application liver-specific expression and efficient delivery of these sequences remain an important objective. We recently reported short-term inhibition of HBV replication in vivo by using helper dependent adenoviral vectors (HD Ads) expressing anti-HBV sequences from a constitutively active cytomegalovirus (CMV) promoter. To develop the use of liver-specific transcription regulatory elements we investigated the utility of the murine transthyretin (MTTR) promoter for expression of anti-HBV primary microRNAs (pri-miRs). HD Ads containing MTTR promoter effected superior expression of anti-HBV pri-miRs in mice compared to HD Ads containing the CMV promoter. MTTR-containing HD Ads resulted in HBV replication knockdown of up to 94% in mice. HD Ads expressing trimeric anti-HBV pri-miRs silenced HBV replication for 5 weeks. We previously showed that the product of the codelivered lacZ gene induces an immune response, and the duration of HBV silencing in vivo is likely to be attenuated by this effect. Nevertheless, expression of anti-HBV pri-miRs from MTTR promoter is well suited to countering HBV replication and development of HD Ads through attenuation of their immunostimulatory effects should advance their clinical utility.

摘要

将RNA干扰（RNAi）应用于对抗乙肝病毒（HBV）复制的研究已促成了潜在治疗序列的识别。然而，在临床应用之前，这些序列的肝脏特异性表达和有效递送仍是一个重要目标。我们最近报道，通过使用从组成型活性巨细胞病毒（CMV）启动子表达抗HBV序列的辅助依赖型腺病毒载体（HD Ads），可在体内短期抑制HBV复制。为了开发肝脏特异性转录调控元件的用途，我们研究了小鼠甲状腺素运载蛋白（MTTR）启动子在抗HBV初级微小RNA（pri-miRs）表达中的效用。与含有CMV启动子的HD Ads相比，含有MTTR启动子的HD Ads在小鼠中实现了抗HBV pri-miRs的更高表达。含MTTR的HD Ads在小鼠中导致HBV复制降低达94%。表达三聚体抗HBV pri-miRs的HD Ads使HBV复制沉默了5周。我们之前表明，共递送的lacZ基因产物会诱导免疫反应，并且这种效应可能会减弱体内HBV沉默的持续时间。尽管如此，从MTTR启动子表达抗HBV pri-miRs非常适合对抗HBV复制，并且通过减弱其免疫刺激作用来开发HD Ads应该会提高它们在临床上的效用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/1d83b63d528d/BMRI2014-718743.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/dde3734adaf9/BMRI2014-718743.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/4a809d99522b/BMRI2014-718743.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/03f5b68e2339/BMRI2014-718743.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/3ed9739263b0/BMRI2014-718743.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/416ff9a4ab51/BMRI2014-718743.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/1d83b63d528d/BMRI2014-718743.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/dde3734adaf9/BMRI2014-718743.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/4a809d99522b/BMRI2014-718743.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/03f5b68e2339/BMRI2014-718743.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/3ed9739263b0/BMRI2014-718743.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/416ff9a4ab51/BMRI2014-718743.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7de2/4066856/1d83b63d528d/BMRI2014-718743.006.jpg

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