Thakur Shikha, Sinhari Apurba, Jain Priti, Jadhav Hemant R
Pharmaceutical Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani, RJ, India.
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India.
Front Pharmacol. 2022 Oct 19;13:1006304. doi: 10.3389/fphar.2022.1006304. eCollection 2022.
It is estimated that the human genome encodes 15% of proteins that are considered to be disease-modifying. Only 2% of these proteins possess a druggable site that the approved clinical candidates target. Due to this disparity, there is an immense need to develop therapeutics that may better mitigate the disease or disorders aroused by non-druggable and druggable proteins or enzymes. The recent surge in approved oligonucleotide therapeutics (OT) indicates the imminent potential of these therapies. Oligonucleotide-based therapeutics are of intermediate size with much-improved selectivity towards the target and fewer off-target effects than small molecules. The OTs include Antisense RNAs, MicroRNA (MIR), small interfering RNA (siRNA), and aptamers, which are currently being explored for their use in neurodegenerative disorders, cancer, and even orphan diseases. The present review is a congregated effort to present the past and present of OTs and the current efforts to make OTs for plausible future therapeutics. The review provides updated literature on the challenges and bottlenecks of OT and recent advancements in OT drug delivery. Further, this review deliberates on a newly emerging approach to personalized treatment for patients with rare and fatal diseases with OT.
据估计，人类基因组编码的蛋白质中有15%被认为具有疾病修饰作用。其中只有2%的蛋白质拥有可成药位点，而获批的临床候选药物正是针对这些位点。由于这种差异，迫切需要开发能够更好地减轻由不可成药和可成药蛋白质或酶引发的疾病或病症的疗法。最近获批的寡核苷酸疗法（OT）的激增表明了这些疗法的巨大潜力。基于寡核苷酸的疗法具有中等大小，对靶点的选择性有了很大提高，且脱靶效应比小分子更少。寡核苷酸疗法包括反义RNA、微小RNA（MIR）、小干扰RNA（siRNA）和适配体，目前正在探索它们在神经退行性疾病、癌症甚至罕见病中的应用。本综述旨在集中呈现寡核苷酸疗法的过去和现在，以及目前为使寡核苷酸疗法成为可行的未来疗法所做的努力。该综述提供了关于寡核苷酸疗法的挑战和瓶颈以及寡核苷酸疗法药物递送方面最新进展的文献。此外，本综述还探讨了一种针对患有罕见致命疾病的患者采用寡核苷酸疗法进行个性化治疗的新出现的方法。
