University of Queensland, School of Biomedical Sciences, Brisbane, Australia.
Expert Opin Drug Deliv. 2010 Mar;7(3):331-9. doi: 10.1517/17425240903512931.
Non-viral gene delivery for the treatment of genetic and non-genetic diseases has been under investigation for several decades, but there has been very little application in patients because of poor gene expression and toxicity.
As gene delivery almost invariably involves endocytosis, many of its limitations are related to compartmentalisation of the transgene within the endosomes. Gene expression enhancers have become an essential part of manipulating endosomal release, as well as protecting transgene from intracellular degradation. However, disruption of the endosomes can also release proteases that have been shown to activate apoptotic pathways.
An understanding of the role that endosomal release plays in the toxicity of gene delivery vehicles will help identify new approaches to minimise adverse effects while enhancing non-viral gene expression.
The future of non-viral gene therapy needs to identify new approaches that limit endosome-induced toxicity while enhancing expression so that a pharmacological response can be reliably observed in vivo.
非病毒基因传递治疗的遗传和非遗传疾病已经研究了几十年，但由于表达不佳和毒性，很少有应用于患者。
由于基因传递几乎总是涉及内吞作用，因此其许多局限性与转染基因在内涵体中的区室化有关。基因表达增强子已成为操纵内涵体释放以及保护转基因免受细胞内降解的重要组成部分。然而，内涵体的破坏也可以释放蛋白酶，已证明这些蛋白酶可以激活凋亡途径。
了解内涵体释放在基因传递载体毒性中的作用将有助于确定新的方法来最小化不良反应，同时增强非病毒基因表达。
非病毒基因治疗的未来需要确定新的方法，以限制内涵体诱导的毒性，同时增强表达，以便在体内可靠地观察到药物反应。
