Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
J Pathol. 2012 Jan;226(2):365-79. doi: 10.1002/path.2993. Epub 2011 Nov 9.
Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology.
合成核酸通常被用作调节基因表达的实验室工具，具有广泛应用于临床的潜力。然而，核酸药物的进展缓慢，在充分了解其对患者护理的影响之前，仍有许多挑战需要克服。反义寡核苷酸 (ASO) 和小干扰 RNA (siRNA) 是两种最广泛用于沉默基因表达的策略。我们首先描述这两种方法，并比较它们在实验室应用中的相对优势和劣势。然后，我们回顾在临床候选药物开发过程中面临的选择以及当前临床试验的现状。在过去的 20 年中，人们对核酸沉默策略的临床开发的态度反复从乐观转向沮丧。我们的目标是提供设计具有稳健性的寡核苷酸研究所需的信息，利用每种寡核苷酸技术的优势。
