Delivering the goods: viral and non-viral gene therapy systems and the inherent limits on cargo DNA and internal sequences
Delivering the goods: viral and non-viral gene therapy systems and the inherent limits on cargo DNA and internal sequences
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DOI：
10.1007/s10709-009-9434-3
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发表时间：
2010-05-01
期刊：
影响因子：
1.5
通讯作者：
Chalmers, Ronald
中科院分区：
文献类型：
--
作者：
Atkinson, Helen;Chalmers, Ronald
病毒一直被认为是人类基因治疗最有前途的工具。然而，鉴于潜在的致命副作用，最初对使用病毒的热情已经失去了光泽。转座子在实验室中与细菌一起使用有很长的历史，并且现在常规地应用于真核模式生物。转座子在人类基因改造中的应用前景，应该证明是一个有用的基因治疗工具包的补充。在这里，我们回顾了病毒的使用和目前的基因治疗方法的局限性，其次是转座子的长度和内部序列的物理性质，这两者都影响转座效率进行了更详细的分析。随着转座子长度的增加，转座减少：这种现象被称为长度依赖性，并对载体货物容量有影响。通过天然DNA的缺失或外源DNA的插入破坏内部序列，可以减少或增强遗传流动性。这些影响可能与宿主因子结合、必需间隔区要求或其他影响有关，但尚未阐明。长度依赖性是一种复杂的现象，不仅由转座子末端之间的距离驱动，而且由宿主蛋白质、转座酶和转座子内编码的DNA序列的性质驱动。
Viruses have long been considered to be the most promising tools for human gene therapy. However, the initial enthusiasm for the use of viruses has been tarnished in the light of potentially fatal side effects. Transposons have a long history of use with bacteria in the laboratory and are now routinely applied to eukaryotic model organisms. Transposons show promise for applications in human genetic modification and should prove a useful addition to the gene therapy tool kit. Here we review the use of viruses and the limitations of current approaches to gene therapy, followed by a more detailed analysis of transposon length and the physical properties of internal sequences, which both affect transposition efficiency. As transposon length increases, transposition decreases: this phenomenon is known as length-dependence, and has implications for vector cargo capacity. Disruption of internal sequences, either via deletion of native DNA or insertion of exogenous DNA, may reduce or enhance genetic mobility. These effects may be related to host factor binding, essential spacer requirements or other influences yet to be elucidated. Length-dependence is a complex phenomenon driven not simply by the distance between the transposon ends, but by host proteins, the transposase and the properties of the DNA sequences encoded within the transposon.