Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute64193110.17816/gc641931ReviewsНаучные обзорыReview ArticleChallenges in developing gene therapy against Duchenne muscular dystrophyПрепятствия на пути к разработке генной терапии мышечной дистрофии Дюшеннаhttps://orcid.org/0009-0007-2296-2031KurshakovaElizaveta V.КуршаковаЕлизавета Владимировна
Russian Federation
kurshakovalv@mail.ruhttps://orcid.org/0000-0001-9465-42133625-4111LevchenkoOlga A.ЛевченкоОльга Александровна
Russian Federation

MD, Cand. Sci. (Medicine)

канд. мед. наук

olevchenko@med-gen.ruhttps://orcid.org/0000-0003-4962-69474926-8347LavrovAlexander V.ЛавровАлександр Вячеславович
Russian Federation

MD, Cand. Sci. (Medicine)

канд. мед. наук

alexandervlavrov@gmail.comResearch Centre for Medical GeneticsМедико-генетический научный центр имени академика Н.П. БочковаMoscow Institute of Physics and TechnologyМосковский физико-технический институт (национальный исследовательский университет)120320250704202520118301511202419022025Copyright ©; 2025, Eco-VectorCopyright ©; 2025, Эко-Вектор2025Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0/https://genescells.ru/2313-1829/article/view/641931

Duchenne muscular dystrophy is a progressive X-linked recessive neuromuscular disorder resulting from pathogenic mutations in the DMD gene, which codes dystrophin. It is one of the essential structural proteins of muscle cells that maintains the integrity of cross-striated muscles. Duchenne muscular dystrophy causes progressive muscular weakness and, as a consequence, reduces life expectancy due to respiratory failure and/or heart failure.

Glucocorticoids are considered the standard of care in Duchenne muscular dystrophy, although they are not highly effective and may lead to numerous adverse effects. For decades, many studies have been focused on finding an effective therapy for Duchenne muscular dystrophy; however, no etiology-oriented product is currently available for patients with Duchenne muscular dystrophy. That being said, the latest studies demonstrate that promising effective gene therapy for Duchenne muscular dystrophy is possible in the near future. The ongoing studies include approaches such as replacement therapy with shortened dystrophin forms and genome editing. Despite high efficacy of the approaches in vitro and in animal models, there is a number of challenges when it comes to treating human patients with Duchenne muscular dystrophy. The first challenge is the gene size — DMD is one of the largest genes, which makes it difficult to load it into viral vectors for delivery. Second, Duchenne muscular dystrophy is caused by over 7000 mutations, so creating universal gene therapies applicable to wide patient populations is problematic. Besides, low efficacy of genetic structure delivery and immune responses — both to the transgene and the viral vector — are a concern. Moreover, long-term sequelae of dystrophin deficiency could persist even if the protein expression is restored. The ongoing studies offer strategies to overcome the limitations above.

This review aims to discuss the current challenges, the solutions to which may become a breakthrough in gene therapy for Duchenne muscular dystrophy and other hereditary diseases.

Мышечная дистрофия Дюшенна (МДД) — это прогрессирующее нервно-мышечное Х-сцепленное рецессивное заболевание, возникающее в результате появления патогенных мутаций в гене DMD, кодирующем белок дистрофин. Это важный структурный белок мышечных клеток, который поддерживает целостность поперечнополосатой мускулатуры. МДД приводит к прогрессирующей мышечной слабости и, как результат, сокращению продолжительности жизни из-за дыхательной и/или сердечной недостаточности.

Стандартом лечения МДД считается применение глюкокортикоидов, которые не являются высокоэффективными и могут быть причиной многих побочных эффектов. В течение десятилетий множество исследований было направлено на поиск эффективного метода терапии, однако в настоящее время для пациентов с МДД не существует лекарства, способного полностью устранить причину заболевания. Тем не менее последние исследования демонстрируют, что создание эффективной и перспективной генной терапии МДД возможно в ближайшем будущем. Такие подходы, как заместительная терапия укороченными формами дистрофина и редактирование генома, активно изучаются в настоящее время, но, хотя некоторые из этих подходов показали высокую эффективность на клеточных культурах и модельных животных, существует ряд препятствий для их эффективного использования при лечении миодистрофии Дюшенна у человека. В первую очередь к этим препятствиям относится размер гена (DMD является одним из крупнейших), что затрудняет его упаковку в вирусные векторы для доставки. Более 7000 различных мутаций служат причиной МДД, что осложняет создание универсальных препаратов генной терапии, которые могли бы быть применимы к большим группам пациентов. Кроме того, серьёзными проблемами являются низкая эффективность доставки генетических конструкций и иммунные ответы как на трансген, так и на вирусный вектор. А долгосрочные последствия дефицита дистрофина могут сохраняться даже при восстановлении экспрессии белка. Несмотря на перечисленные проблемы, в текущих исследованиях предлагаются различные стратегии для преодоления этих ограничений.

Целью данного обзора является обсуждение существующих проблем, решение которых может стать значительным шагом к разработке генной терапии МДД и многих других наследственных заболеваний.

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