Atkinson Helen, Chalmers Ronald
School of Biomedical Sciences, University of Nottingham, Queen's Medical Center, Nottingham NG7 2UH, UK.
Genetica. 2010 May;138(5):485-98. doi: 10.1007/s10709-009-9434-3. Epub 2010 Jan 19.
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.
长期以来，病毒一直被认为是人类基因治疗最具前景的工具。然而，鉴于可能存在的致命副作用，人们最初对使用病毒的热情有所减退。转座子在实验室中与细菌的使用历史悠久，现在已常规应用于真核模式生物。转座子在人类基因改造应用中显示出前景，应该会成为基因治疗工具包中一个有用的补充。在这里，我们回顾了病毒的使用以及当前基因治疗方法的局限性，随后更详细地分析了转座子长度和内部序列的物理特性，这两者都会影响转座效率。随着转座子长度增加，转座作用会降低：这种现象被称为长度依赖性，对载体的有效负载能力有影响。通过删除天然DNA或插入外源DNA对内部分子序列的破坏，可能会降低或增强基因移动性。这些影响可能与宿主因子结合、必需间隔区要求或其他有待阐明的影响因素有关。长度依赖性是一种复杂的现象，其驱动因素不仅仅是转座子两端之间的距离，还包括宿主蛋白、转座酶以及转座子内编码的DNA序列的特性。
