Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, Edmonton, AB, Canada.
Methods Mol Biol. 2020;2176:3-19. doi: 10.1007/978-1-0716-0771-8_1.
Gapmers are antisense oligonucleotides composed of a central DNA segment flanked by nucleotides of modified chemistry. Hybridizing with transcripts by sequence complementarity, gapmers recruit ribonuclease H and induce target RNA degradation. Since its concept first emerged in the 1980s, much work has gone into developing gapmers for use in basic research and therapy. These include improvements in gapmer chemistry, delivery, and therapeutic safety. Gapmers have also successfully entered clinical trials for various genetic disorders, with two already approved by the U.S. Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.
反义寡核苷酸由一段中心 DNA 序列组成，两侧为修饰化学的核苷酸。通过序列互补与转录本杂交，反义寡核苷酸募集核糖核酸酶 H 并诱导靶 RNA 降解。自 20 世纪 80 年代概念首次出现以来，人们进行了大量工作来开发用于基础研究和治疗的反义寡核苷酸。这些改进包括反义寡核苷酸化学、递药和治疗安全性的改进。反义寡核苷酸也已成功进入各种遗传疾病的临床试验，其中两种已被美国食品和药物管理局批准用于治疗家族性高胆固醇血症和转甲状腺素淀粉样变性相关多发性神经病。在这里，我们回顾了反义寡核苷酸从概念到成熟的早期发展过程中的相关事件，并简要总结了它们在治疗中的应用前景。
