Utrophin instead of dystrophin
Russian scientists have proposed a new method of therapy for Duchenne myodystrophy
Press Center of the Ministry of Education and Science
The researchers found out that as a means of safe and effective gene therapy of the disease, the protein utrophin can be used, duplicating the functions of dystrophin, the deficiency of which causes such a hereditary disease as Duchenne myodystrophy. Thus, scientists of the Institute of Gene Biology (IBG) of the Russian Academy of Sciences subordinate to the Ministry of Education and Science of the Russian Academy of Sciences have figured out how to solve one of the main problems that arise when using gene replacement therapy for the treatment of Duchenne myodystrophy. The work of scientists is supported by the Ministry of Education and Science of Russia.
Duchenne myodystrophy (MDD) is a severe hereditary disease characterized by progressive muscle weakness and muscle destruction. The disease is caused by various mutations in the DMD gene (dystrophin gene). MDD therapy is aimed at restoring the expression of dystrophin, a process during which hereditary information is converted into RNA and then into protein.
A mutation in a gene can lead to the development of a hereditary disease. It is possible to alleviate or even defeat the disease by delivering a working copy of the broken gene to the cells. The couriers for the gene are adeno-associated viruses (abbreviated AAV). Such viruses have many useful properties, for example, they are not able to reproduce independently and do not cause diseases in the human body. AAV can penetrate dividing and non-dividing cells. In addition, up to 96% of their own genome can be removed from these viruses without consequences.
Currently, several drugs acting at the splicing level have been approved for the treatment of MDD: at the time of formation of RNA with a mutation in patients' cells, the drugs bind to the mutant site and prevent their participation in further protein formation. A shortened, but functional dystrophin is formed. Unlike gene therapy with AAV, such drugs must be taken throughout life. In addition, they are suitable only for certain groups of patients with certain mutations in the dystrophin gene.
Gene therapy preparations based on the use of adeno-associated viruses (AAV) to deliver a shortened version of the dystrophin gene are at the stage of clinical trials. Such drugs are universal, and they can be used for all patients, and only one injection is required to stop the development of the disease. One of the main drawbacks of this therapeutic approach is the possible immune response to the protein dystrophin in patients with MDD: the body considers the shortened dystrophin, which was previously absent in the cells, foreign and gets rid of it.
Scientists of the Laboratory of Modeling and therapy of hereditary diseases of the IBG RAS proposed instead of dystrophin to deliver the protein utrophin in a shortened form (microutrophin), 73% identical to dystrophin in amino acid composition. Scientists have found that the use of utrophin can reduce the immune response to the injected drug. Researchers have constructed an AAV vector encoding human microtrophin optimized for improved expression in muscle and heart cells.
"The therapeutic effect of the resulting viral drug was tested on model mice with Duchenne myodystrophy. We were able to show an improvement in the functional properties of muscle tissue, a decrease in creatine kinase levels and a low level of immune response compared to the response caused by the introduction of a similar construct with microdystrophin. The toxicity study also revealed no adverse changes," said Tatiana Egorova, a researcher at the Laboratory of Modeling and Therapy of Hereditary Diseases of the IBG RAS.
Currently, additional studies are being conducted in the laboratory to increase the expression of therapeutic genes in muscle tissue in order to reduce the required dose of the drug.
The results of the work were published in the journal Scientific Reports (Starikova et al., Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression).
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