Kaur Punit, Nagaraja Ganachari M, Asea Alexzander
Division of Investigative Pathology, College of Medicine, Scott & White Memorial Hospital and Clinic, Temple, TX, USA.
Methods Mol Biol. 2011;787:121-36. doi: 10.1007/978-1-61779-295-3_10.
Elevated heat shock protein 27 (Hsp27) expression has been found in a number of tumors, including breast, prostate, gastric, uterine, ovarian, head and neck, and tumor arising from the nervous system and urinary system, and determined to be a predictor of poor clinical outcome. Although the mechanism of action of Hsp27 has been well documented, there are currently no available inhibitors of Hsp27 in clinical trials. RNA interference (RNAi) has the potential to offer more specificity and flexibility than traditional drugs to silence gene expression. Not surprisingly, RNAi has become a major focus for biotechnology and pharmaceutical companies, which are now in the early stages of developing RNAi therapeutics, mostly based on short interfering RNA (siRNAs), to target viral infection, cancer, hypercholesterolemia, cardiovascular disease, macular degeneration, and neurodegenerative diseases. However, the critical issues associated with RNAi as a therapeutic are delivery, specificity, and stability of the RNAi reagents. To date, the delivery is currently considered the biggest hurdle, as the introduction of siRNAs systemically into body fluids can result in their degradation, off-target effects, and immune detection. In this chapter, we discuss a method of combined lentiviral and RNAi-based technology for the delivery and permanent silencing of the hsp25 gene.
在包括乳腺癌、前列腺癌、胃癌、子宫癌、卵巢癌、头颈癌以及神经系统和泌尿系统肿瘤在内的多种肿瘤中，均发现热休克蛋白27（Hsp27）表达升高，并被确定为临床预后不良的一个预测指标。尽管Hsp27的作用机制已有充分记载，但目前尚无Hsp27抑制剂进入临床试验阶段。与传统药物相比，RNA干扰（RNAi）在沉默基因表达方面具有更高的特异性和灵活性。不出所料，RNAi已成为生物技术和制药公司的主要关注焦点，这些公司目前正处于开发RNAi疗法的早期阶段，主要基于小干扰RNA（siRNA）来靶向病毒感染、癌症、高胆固醇血症、心血管疾病、黄斑变性和神经退行性疾病。然而，与RNAi作为一种治疗方法相关的关键问题是RNAi试剂的递送、特异性和稳定性。迄今为止，递送目前被认为是最大的障碍，因为将siRNA全身引入体液会导致其降解、脱靶效应和免疫检测。在本章中，我们将讨论一种基于慢病毒和RNAi技术相结合的方法，用于hsp25基因的递送和永久沉默。
