RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01604, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01604, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01604, USA; VIDE Program, University of Massachusetts Medical School, Worcester, MA 01604, USA.
Mol Ther. 2021 Apr 7;29(4):1382-1394. doi: 10.1016/j.ymthe.2020.12.023. Epub 2020 Dec 19.
Oligonucleotide therapeutics hold promise for the treatment of muscle- and heart-related diseases. However, oligonucleotide delivery across the continuous endothelium of muscle tissue is challenging. Here, we demonstrate that docosanoic acid (DCA) conjugation of small interfering RNAs (siRNAs) enables efficient (~5% of injected dose), sustainable (>1 month), and non-toxic (no cytokine induction at 100 mg/kg) gene silencing in both skeletal and cardiac muscles after systemic injection. When designed to target myostatin (muscle growth regulation gene), siRNAs induced ~55% silencing in various muscle tissues and 80% silencing in heart, translating into a ~50% increase in muscle volume within 1 week. Our study identifies compounds for RNAi-based modulation of gene expression in skeletal and cardiac muscles, paving the way for both functional genomics studies and therapeutic gene modulation in muscle and heart.
寡核苷酸疗法有望治疗肌肉和心脏相关疾病。然而，将寡核苷酸递送到肌肉组织的连续内皮是具有挑战性的。在这里，我们证明了小分子干扰 RNA（siRNA）与二十二烷酸（DCA）的缀合能够在全身注射后在骨骼肌和心肌中实现高效（约注射剂量的 5%）、持续（>1 个月）和无毒（100mg/kg 时无细胞因子诱导）的基因沉默。当设计用于靶向肌肉生长调节基因肌生成素时，siRNA 在各种肌肉组织中诱导了约 55%的沉默，在心脏中诱导了 80%的沉默，导致肌肉体积在 1 周内增加了约 50%。我们的研究确定了用于在骨骼肌和心肌中基于 RNAi 调节基因表达的化合物，为功能基因组学研究和肌肉和心脏的治疗性基因调节铺平了道路。
Zotero 插件
