Keating Michael F, Drew Brian G, Calkin Anna C
Lipid Metabolism and Cardiometabolic Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Molecular Metabolism and Ageing Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Front Physiol. 2022 Jan 28;13:839471. doi: 10.3389/fphys.2022.839471. eCollection 2022.
Synthetic oligonucleotide technologies are DNA or RNA based molecular compounds that are utilized to disrupt gene transcription or translation in target tissues or cells. Optimally, oligonucleotides are 10-30 base pairs in length, and mediate target gene suppression through directed sequence homology with messenger RNA (mRNA), leading to mRNA degradation. Examples of specific oligonucleotide technologies include antisense oligonucleotides (ASO), short hairpin RNAs (shRNA), and small interfering RNAs (siRNA). and studies that model obesity related disorders have demonstrated that oligonucleotide technologies can be implemented to improve the metabolism of cells and tissues, exemplified by improvements in fat utilization and hepatic insulin signaling, respectively. Oligonucleotide therapy has also been associated with reductions in lipid accumulation in both the liver and adipose tissue in models of diet-induced obesity. Recent advances in oligonucleotide technologies include the addition of chemical modifications such as N-acetylgalactosamine (GalNAc) conjugates that have been successful at achieving affinity for the liver, in turn improving specificity, and thus reducing off target effects. However, some challenges are still yet to be overcome relating to hepatic injury and off-target effects that have been reported with some compounds, including ASOs. In summary, oligonucleotide-based therapies are an effective tool to elucidate mechanistic insights into metabolic pathways and provide an attractive avenue for translational research into the clinic.
合成寡核苷酸技术是基于DNA或RNA的分子化合物，用于破坏靶组织或细胞中的基因转录或翻译。理想情况下，寡核苷酸长度为10 - 30个碱基对，并通过与信使RNA（mRNA）的定向序列同源性介导靶基因抑制，导致mRNA降解。特定寡核苷酸技术的实例包括反义寡核苷酸（ASO）、短发夹RNA（shRNA）和小干扰RNA（siRNA）。模拟肥胖相关疾病的研究表明，寡核苷酸技术可用于改善细胞和组织的代谢，分别以脂肪利用和肝脏胰岛素信号传导的改善为例。在饮食诱导肥胖模型中，寡核苷酸疗法还与肝脏和脂肪组织中脂质积累的减少有关。寡核苷酸技术的最新进展包括添加化学修饰，如N - 乙酰半乳糖胺（GalNAc）缀合物，这些缀合物已成功实现对肝脏的亲和力，进而提高特异性，从而减少脱靶效应。然而，与某些化合物（包括ASO）报道的肝损伤和脱靶效应相关的一些挑战仍有待克服。总之，基于寡核苷酸的疗法是阐明代谢途径机制见解的有效工具，并为临床转化研究提供了一条有吸引力的途径。
