Stages of research and development of therapeutic approaches for Duchenne myodystrophy. Part II: etiotropic approaches

Abstract

Duchenne muscular dystrophy is one of the most common inherited muscular dystrophies. The cause of this disease with an X‑linked recessive type of inheritance is mutations in the DMD gene, leading to the absence of the dystrophin protein this gene encodes or its impaired function. Loss of dystrophin leads to severe degenerative processes in patients, especially in muscle tissue, with impaired muscle function, loss of ability to move independently, respiratory failure, cardiomyopathies, etc.The collective efforts of many researchers over the years since the 19th century, when the diseases was described, not allowed to achieve a cure or significantly influencing the trajectory of the illness. The only notable impact on the disease course has come with the integration of corticosteroid medications into Duchenne muscular dystrophy therapy. While their application can decelerate disease progression and extend the average life expectancy up to 30–40 years, it comes with substantial adversely affects influencing patients’ quality of life.Certain hopes were associated in recent decades with the development of etiotropic therapy for Duchenne muscular dystrophy, aimed at restoration of the dystrophin’s function. Some of such approaches were based on the overcoming of the effect of premature stop codons in the DMD gene using aminoglycoside antibiotics, ataluren, etc. Several subsequent studies were conducted to explore the applicability of exon‑skipping approaches in the dystrophin gene, aimed at excluding exons carrying pathogenic genetic variants. The rationale for these studies was the available information about a milder course of the disease associated with a truncated but functional dystrophin. The possibility of the pathology correction by means of introduction of the exogenous functional DMD gene copy from the outside (gene replacement therapy) has been under study since the beginning of the 20th century. One of the most promising directions in recent years was the development of approaches related to genome editing, which, unlike the methods mentioned above, allows for the permanent correction of the underlying cause of genetic diseases. Some of corresponding drugs have already received approval, while others, related to gene therapy, are at the stage of clinical trials.