Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC137910.15690/vramn1379NEUROLOGY AND NEUROSURGERY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ НЕВРОЛОГИИ И НЕЙРОХИРУРГИИResearch ArticleProspects for the Etiotropic Treatment of DysferlinopathyПерспективы этиотропного лечения дисферлинопатийhttps://orcid.org/0000-0002-8954-73309922-7412IvanovaAlisa V.ИвановаАлиса Владимировна
Russian Federation

Junior Researcher

младший научный сотрудник лаборатории редактирования генома

bioyoghurtneo@yandex.ruhttps://orcid.org/0000-0002-1558-30486884-6170SmirnikhinaSvetlana A.СмирнихинаСветлана Анатольевна
Russian Federation

MD, PhD

кандидат медицинских наук, заведующая лабораторией редактирования генома

smirnikhinas@gmail.comhttps://orcid.org/0000-0003-4962-69474926-8347LavrovAlexander V.ЛавровАлександр Вячеславович
Russian Federation

Leading Research Scientist, MD, PhD

кандидат медицинских наук, ведущий научный сотрудник лаборатории редактирования генома

alexandervlavrov@gmail.comResearch Centre for Medical GeneticsМедико-генетический научный центр имени академика Н.П. Бочкова030920217633073161906202001072021Copyright ©; 2021, "Paediatrician" Publishers LLCCopyright ©; 2021, Издательство "Педиатръ"2021"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/1379

Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such as Miyoshi myopathy with primary lesion of the distal fragments of the lower extremities and limb-gridle muscular dystrophy type 2B with primary lesion of the proximal fragments of both the lower and upper limbs, also distal myopathy with anterior tibial onset (DMAT). Nowdays, there are various pathogenetic and symptomatic treatments for hereditary muscular dystrophies but there are very few registered drugs for the etiological treatment of these diseases. This review discusses the main modern methods of gene therapy that can be used to treat dysferlinopathies, such as stop-codon passing, exon skipping, overexpression of other genes, gene transfer, splicosome-mediated trans-splicing, and also describes the latest experimental studies using these methods. In conclusion, exon-skipping and trans-splicing have been identified as the most optimal approaches in the treatment of muscular dystrophies, in particular dysferlinopathies.

Дисферлинопатии относятся к фенотипически гетерогенной группе нервно-мышечных заболеваний, причиной которых являются мутации в гене DYSF, вследствие которых нарушается экспрессия белка дисферлина в клетках скелетной мышечной ткани человека. Патологии носят аутосомно-рецессивный характер наследования, распространенность составляет 1:200 000. К дисферлинопатиям относятся такие заболевания, как миопатия Миоши с первичным поражением дистальных фрагментов нижних конечностей и поясно-конечностная мышечная дистрофия типа 2Б с первичным поражением проксимальных фрагментов и нижних, и верхних конечностей, а также дистальная миопатия переднего ложа голени (ДМПЛГ). На сегодняшний день существуют различные патогенетические и симптоматические способы терапии наследственных мышечных дистрофий, однако очень мало зарегистрированных препаратов для этиологического лечения этих заболеваний. В настоящем обзоре рассмотрены основные современные методы генной терапии, которые могут быть применены в целях лечения дисферлинопатий, такие как прохождение стоп-кодона, пропуск экзонов, оверэкспрессия других генов, перенос гена, сплайсосомо-опосредованный транссплайсинг, а также описаны последние экспериментальные исследования с использованием этих методов. В заключение экзон-скиппинг и транс-сплайсинг выделены как наиболее оптимальные подходы в терапии миодистрофий, в частности дисферлинопатий.

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