Prakash Satya, Malhotra Meenakshi, Rengaswamy Venkatesh
Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, Artificial Cells and Organs Research Center, McGill University, Montreal, QC, Canada.
Methods Mol Biol. 2010;623:211-29. doi: 10.1007/978-1-60761-588-0_14.
Linking genes with the underlying mechanisms of diseases is one of the biggest challenges of genomics-driven drug discovery research. Designing an inhibitor for any neurodegenerative disease that effectively halts the pathogenicity of the disease is yet to be achieved. The challenge lies in crossing the blood-brain barrier (BBB)/blood-cerebrospinal fluid barrier (BCSFB) to reach the catalytic pockets of the enzyme/protein involved in the molecular mechanism of the disease process. Designing siRNA with exquisite specificity may result in selective suppression of the disease-linked gene. Although siRNA is the most promising method, it loses its potency in downregulating the gene due to its inherent instability, off-target effects, and lack of on-target effective delivery systems. Viral as well as nonviral delivery methods have been effectively tested in vivo for silencing of molecular targets and have resulted in significant efficacy in animal models of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anxiety, depression, encephalitis, glioblastoma, Huntington's disease, neuropathic pain, and spinocerebellar ataxia. To realize the full therapeutic potential of siRNA for neurodegenerative diseases, we need to overcome many hurdles and challenges such as selecting suitable tissue-specific delivery vectors, minimizing the off-target effects, and achieving distribution in sufficient concentrations at the target tissue without any side effects. Cationic nanoparticle-mediated targeted siRNA delivery for therapeutic purposes has gained considerable clinical importance as a result of its promising efficacy.
将基因与疾病的潜在机制联系起来是基因组学驱动的药物发现研究面临的最大挑战之一。设计一种能有效阻止任何神经退行性疾病致病性的抑制剂尚未实现。挑战在于穿越血脑屏障（BBB）/血脑脊液屏障（BCSFB），以到达参与疾病过程分子机制的酶/蛋白质的催化位点。设计具有高度特异性的小干扰RNA（siRNA）可能会导致对疾病相关基因的选择性抑制。尽管siRNA是最有前景的方法，但由于其固有的不稳定性、脱靶效应以及缺乏靶向有效递送系统，它在下调基因方面失去了效力。病毒和非病毒递送方法已在体内有效测试用于沉默分子靶点，并在阿尔茨海默病、肌萎缩侧索硬化症（ALS）、焦虑症、抑郁症、脑炎、胶质母细胞瘤、亨廷顿舞蹈病、神经性疼痛和脊髓小脑共济失调的动物模型中取得了显著疗效。为了实现siRNA对神经退行性疾病的全部治疗潜力，我们需要克服许多障碍和挑战，如选择合适的组织特异性递送载体、最小化脱靶效应以及在靶组织中以足够浓度分布且无任何副作用。由于其有前景的疗效，阳离子纳米颗粒介导的靶向siRNA递送用于治疗目的已获得相当大的临床重要性。
