Skopenkova V V, Egorova T V, Bardina M V
Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia.
Marlin Biotech LLC, Moscow, 121205 Russia.
Acta Naturae. 2021 Jan-Mar;13(1):47-58. doi: 10.32607/actanaturae.11063.
Many genetic diseases that are responsible for muscular disorders have been described to date. Gene replacement therapy is a state-of-the-art strategy used to treat such diseases. In this approach, the functional copy of a gene is delivered to the affected tissues using viral vectors. There is an urgent need for the design of short, regulatory sequences that would drive a high and robust expression of a therapeutic transgene in skeletal muscles, the diaphragm, and the heart, while exhibiting limited activity in non-target tissues. This review focuses on the development and improvement of muscle-specific promoters based on skeletal muscle α-actin, muscle creatine kinase, and desmin genes, as well as other genes expressed in muscles. The current approaches used to engineer synthetic muscle-specific promoters are described. Other elements of the viral vectors that contribute to tissue-specific expression are also discussed. A special feature of this review is the presence of up-to-date information on the clinical and preclinical trials of gene therapy drug candidates that utilize muscle-specific promoters.
迄今为止，已经描述了许多导致肌肉疾病的遗传疾病。基因替代疗法是用于治疗此类疾病的一种先进策略。在这种方法中，使用病毒载体将基因的功能拷贝递送至受影响的组织。迫切需要设计短的调控序列，这些序列能够在骨骼肌、膈肌和心脏中驱动治疗性转基因的高表达和稳定表达，同时在非靶组织中表现出有限的活性。本综述重点关注基于骨骼肌α-肌动蛋白、肌肉肌酸激酶和结蛋白基因以及在肌肉中表达的其他基因的肌肉特异性启动子的开发和改进。描述了用于构建合成肌肉特异性启动子的当前方法。还讨论了病毒载体中有助于组织特异性表达的其他元件。本综述的一个特色是提供了利用肌肉特异性启动子的基因治疗候选药物的临床和临床前试验的最新信息。
