School of Pharmacy, University of Waterloo, 10 Victoria St. S, Kitchener (ON) N2G 1C5, Canada.
Curr Drug Deliv. 2011 May;8(3):235-44. doi: 10.2174/156720111795256174.
Gene therapy holds the promise of correcting a genetic defect. It can be achieved with the introduction of a normal wild-type transgene into specific cells of the patient where the endogenous gene is underexpressing or by the introduction of a therapeutic agent, such as, antisense oligonucleotides (AON) or small interfering RNA (siRNA) to inhibit transcription and/or translation of an overexpressing endogenous gene or a cancer causing oncogene. Gene therapy has been utilized for vaccination and for the treatment of several diseases, such as, cancer, viral infections and dermatological diseases. However, there are many hurdles to overcome in developing effective gene-based therapeutics, including cellular barriers, enzymatic degradation and rapid clearance after administration. Successful transfer of nucleic acids (e.g. plasmid DNA, AON, siRNA, small hairpin RNA and micro RNA) into cells usually relies on the use of efficient carriers, commonly viral or non-viral vectors. Presently, viral vectors are more efficient than non-viral systems. However, immunogenicity, inflammatory reactions and problems associated with scale-up limit their clinical use. The ideal carriers for gene delivery should be safe and yet ensure that the DNA/RNA survives the extra- and intracellular environment and efficiently transfer to the appropriate cellular compartments. This review discusses some of the strategies that have been employed to overcome the barriers towards successful gene delivery.
基因治疗有望纠正遗传缺陷。它可以通过将正常的野生型转基因引入患者特定的细胞中实现，在这些细胞中，内源性基因表达不足，或者通过引入治疗剂，如反义寡核苷酸（AON）或小干扰 RNA（siRNA），来抑制过度表达的内源性基因或致癌基因的转录和/或翻译。基因治疗已被用于疫苗接种和治疗多种疾病，如癌症、病毒感染和皮肤病。然而，在开发有效的基于基因的治疗方法方面存在许多障碍，包括细胞屏障、酶降解和给药后快速清除。核酸（如质粒 DNA、AON、siRNA、短发夹 RNA 和 micro RNA）有效转入细胞通常依赖于高效载体的使用，通常是病毒或非病毒载体。目前，病毒载体比非病毒系统更有效。然而，免疫原性、炎症反应和与规模扩大相关的问题限制了它们的临床应用。理想的基因传递载体应该是安全的，同时确保 DNA/RNA 能够在细胞外和细胞内环境中存活，并有效地转移到适当的细胞隔室中。本文综述了一些已被用于克服成功基因传递障碍的策略。
