Variables and strategies in development of therapeutic post-transcriptional gene silencing agents.
Variables and strategies in development of therapeutic post-transcriptional gene silencing agents.
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DOI：
10.1155/2011/531380
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发表时间：
2011
影响因子：
1.9
通讯作者：
Abdelmaksoud HE
中科院分区：
文献类型：
--
作者：
Sullivan JM;Yau EH;Kolniak TA;Sheflin LG;Taggart RT;Abdelmaksoud HE
转录后基因沉默（PTGS）试剂，如核酶、RNA干扰和反义，在人类视网膜变性的基因治疗中具有巨大的潜力。这些技术用于敲低特定靶RNA及其同源蛋白。疾病靶mRNA可以是引起常染色体显性视网膜变性的突变mRNA或在某些疾病中过表达的正常mRNA。所有PTGS技术都依赖于PTGS配体与靶RNA的初始关键退火事件。该事件要求PTGS试剂处于能够支持杂交的构象状态，并且靶标具有大的且可接近的单链平台以允许快速退火，尽管这样的平台是罕见的。我们解决了目前限制PTGS治疗发展的生物复杂性，特别强调影响细胞性能的生物物理变量。我们解决了不同的策略，可用于开发的PTGS剂用于治疗翻译。这些问题通常适用于开发用于视网膜、眼部或全身性疾病的PTGS试剂。这篇综述应有助于感兴趣的读者迅速了解PTGS开发中的关键变量，并促进此类药物针对临床感兴趣的新靶点的初步设计和测试。
Post-transcriptional gene silencing (PTGS) agents such as ribozymes, RNAi and antisense have substantial potential for gene therapy of human retinal degenerations. These technologies are used to knockdown a specific target RNA and its cognate protein. The disease target mRNA may be a mutant mRNA causing an autosomal dominant retinal degeneration or a normal mRNA that is overexpressed in certain diseases. All PTGS technologies depend upon the initial critical annealing event of the PTGS ligand to the target RNA. This event requires that the PTGS agent is in a conformational state able to support hybridization and that the target have a large and accessible single-stranded platform to allow rapid annealing, although such platforms are rare. We address the biocomplexity that currently limits PTGS therapeutic development with particular emphasis on biophysical variables that influence cellular performance. We address the different strategies that can be used for development of PTGS agents intended for therapeutic translation. These issues apply generally to the development of PTGS agents for retinal, ocular, or systemic diseases. This review should assist the interested reader to rapidly appreciate critical variables in PTGS development and facilitate initial design and testing of such agents against new targets of clinical interest.
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