Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
R&D Center, Helixmith Co., Ltd., Gangseo-gu, Republic of Korea.
Hum Gene Ther. 2022 Dec;33(23-24):1305-1314. doi: 10.1089/hum.2022.103.
Insulin-like growth factor-1 (IGF-1) plays a significant role in the development of various organs, and several studies have suggested that IGF-1 isoforms, IGF-1 Ea and IGF-1 Ec, are expressed in skeletal muscle to control its growth. In this study, we designed a novel nucleotide sequence, IGF-1-X10, consisting of IGF-1 exons and introns to simultaneously express both IGF-1 Ea and IGF-1 Ec. When transfected into human cells, the expression of both isoforms was observed at the transcript and protein levels. In an animal study, intramuscular injection of plasmid DNA comprising IGF-1-X10 induced the expression of IGF-1 Ea and IGF-1 Ec, leading to the production of functional IGF-1 protein. Finally, the efficacy of this plasmid DNA was tested in a cardiotoxin (CTX)-mediated muscle injury model and age-related muscle atrophy model. We found that IGF-1-X10 increased the muscle mass and controlled several key factors involved in the muscle atrophy program in both models. Taken together, these data suggest that IGF-1-X10 may be utilized in the form of gene therapy for the treatment of various muscle diseases related to IGF-1 deficiency.
胰岛素样生长因子-1（IGF-1）在各种器官的发育中起着重要作用，有几项研究表明，IGF-1 同工型 IGF-1 Ea 和 IGF-1 Ec 在骨骼肌中表达，以控制其生长。在本研究中，我们设计了一种新型核苷酸序列 IGF-1-X10，由 IGF-1 外显子和内含子组成，以同时表达 IGF-1 Ea 和 IGF-1 Ec。当转染入人体细胞时，在转录和蛋白质水平上均观察到两种同工型的表达。在动物研究中，肌肉内注射包含 IGF-1-X10 的质粒 DNA 诱导 IGF-1 Ea 和 IGF-1 Ec 的表达，从而产生功能性 IGF-1 蛋白。最后，在心肌毒素（CTX）介导的肌肉损伤模型和与年龄相关的肌肉萎缩模型中测试了这种质粒 DNA 的疗效。我们发现 IGF-1-X10 增加了肌肉质量，并控制了这两种模型中与 IGF-1 缺乏相关的肌肉萎缩程序中的几个关键因素。总之，这些数据表明，IGF-1-X10 可作为基因治疗的形式用于治疗与 IGF-1 缺乏相关的各种肌肉疾病。
