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 -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.

Background: Adeno-associated virus (AAV) vector-mediated gene transfer is an emerging treatment strategy for severe cardiac disorders with genetic etiology. We refined the AAV toolkit to achieve efficient and selective expression of the therapeutic transgene in mouse hearts. Methods: Using vectors with a reporter transgene, we evaluated AAV administration routes, AAV serotype tropism to the myocardium, and cardiospecific promoters. Results: We showed that systemic AAV administration provides potent delivery and uniform transduction of cardiac tissue, outperforming localized injection techniques. The MyoAAV 2A capsid variant enabled an improved heart-to-liver transduction ratio compared to the parental AAV9 serotype. Screening a panel of cardiac and pan-muscular promoters in vitro and in vivo verified the superiority of the cardiac troponin T (cTnT) promoter for robust heart-specific transgene expression. Finally, we demonstrated that the cumulative properties of systemic AAV delivery, the MyoAAV 2A serotype, and the cTnT promoter allowed for efficient cardiac synthesis of the therapeutic transgene—an artificial miRNA designed for the gene suppression strategy of FLNC-related cardiomyopathy. Conclusions: Our findings establish an effective AAV approach for transgene transfer into the mouse heart and promote the development of gene therapy for cardiac disorders.