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首页> 外文期刊>Human gene therapy. Clinical development >Optimizing Retroviral Gene Expression for Effective Therapies
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Optimizing Retroviral Gene Expression for Effective Therapies

机译：优化逆转录病毒基因表达以进行有效治疗

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摘要

With their ability to integrate their genetic material into the target cell genome, retroviral vectors (RV) of both the gamma-retroviral (y-RV) and lentiviral vector (LV) classes currently remain the most efficient and thus the system of choice for achieving transgene retention and therefore potentially long-term expression and therapeutic benefit. However, y-RV and LV integration comes at a cost in that transcription units will be present within a native chromatin environment and thus be subject to epigenetic effects (DNA methylation, histone modifications) that can negatively impact on their function. Indeed, highly variable expression and silencing of y-RV and LV transgenes especially resulting from promoter DNA methylation is well documented and was the cause of the failure of gene therapy in a clinical trial for X-linked chronic granulomatous disease. This review will critically explore the use of different classes of genetic control elements that can in principle reduce vector insertion site position effects and epigenetic-mediated silencing. These transcriptional regulatory elements broadly divide themselves into either those with a chromatin boundary or border function (scaffold/matrix attachment regions, insulators) or those with a dominant chromatin remodeling and transcriptional activating capability (locus control regions,, ubiquitous chromatin opening elements). All these types of elements have their strengths and weaknesses within the constraints of a y-RV and LV backbone, showing varying degrees of efficacy in improving reproducibility and stability of transgene function. Combinations of boundary and chromatin remodeling; transcriptional activating elements, which do not impede vector production; transduc-tion efficiency; and stability are most likely to meet the requirements within a gene therapy context especially when targeting a stem cell population.
机译：由于具有将遗传物质整合到靶细胞基因组中的能力，目前γ-逆转录病毒（y-RV）和慢病毒载体（LV）的逆转录病毒载体（RV）仍然是最有效的，因此是实现该目标的首选系统转基因保留，因此可能具有长期表达和治疗益处。但是，y-RV和LV整合的代价是转录单元将存在于天然染色质环境中，因此会受到表观遗传效应（DNA甲基化，组蛋白修饰）的影响，会对它们的功能产生负面影响。确实，y-RV和LV转基因的高度可变表达和沉默，尤其是由启动子DNA甲基化引起的，已被充分证明，并且是在X连锁慢性肉芽肿病的临床试验中基因治疗失败的原因。这项审查将批判性地探索不同种类的基因控制元件的使用，这些原则上可以减少载体插入位点的位置影响和表观遗传介导的沉默。这些转录调控元件可将自身大致分为具有染色质边界或边界功能的那些（支架/基质附着区域，绝缘子）或具有主导的染色质重塑和转录激活能力的区域（基因座控制区，无处不在的染色质开放元件）。所有这些类型的元件在y-RV和LV主链的约束下都有其优缺点，显示出在改善转基因功能的可再现性和稳定性方面的不同程度的功效。边界和染色质重塑的组合;不阻碍载体产生的转录激活元件;转换效率;特别是针对干细胞群体时，稳定性和稳定性最有可能满足基因治疗的要求。

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