biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2024-24-2-123-139biopreparat-572Research ArticleТЕМА НОМЕРА: ВЫСОКОТЕХНОЛОГИЧНЫЕ ЛЕКАРСТВЕННЫЕ ПРЕПАРАТЫISSUE TOPIC: ADVANCED THERAPY MEDICINAL PRODUCTSГенная терапия наследственных заболеваний на основе аденоассоциированных вирусных векторов: современные проблемы применения и пути их решенияAdeno-associated virus vector-based gene therapy for hereditary diseases: current problems of application and approaches to solve themhttps://orcid.org/0000-0002-3346-3242ЕгороваТ. В.EgorovaT. V.

Егорова Татьяна Владимировна, канд. биол. наук

ул. Вавилова, д. 34/5, Москва, 119334

Триумфальный проезд, д. 1, пгт. Сириус, Краснодарский край, 354340

Tatiana V. Egorova, Cand. Sci. (Biol.)

34/5 Vavilov St., Moscow 119334

1 Triumfalny Dr., Sirius urban-type settlement, Krasnodar Region 354340

dimitrieva.ta@gmail.comhttps://orcid.org/0000-0001-5552-5419ПискуновА. А.PiskunovA. A.

Пискунов Александр Александрович, канд. биол. наук

ул. Владимирская, д. 14, пос. Вольгинский, Петушинский район, Владимирская область, 601125

Aleksandr A. Piskunov, Cand. Sci. (Biol.)

14 Vladimirskaya St., Volginsky, Petushinskiy District, Vladimir Region 601125

piskunov@generium.ruhttps://orcid.org/0000-0003-2695-8869ПотеряевД. А.PoteryaevD. A.

Потеряев Дмитрий Александрович, канд. биол. наук

ул. Владимирская, д. 14, пос. Вольгинский, Петушинский район, Владимирская область, 601125

Dmitry A. Poteryaev, Cand. Sci. (Biol.)

14 Vladimirskaya St., Volginsky, Petushinskiy District, Vladimir Region 601125

poteryaev@generium.ruФедеральное государственное бюджетное учреждение науки Институт биологии гена Российской академии наук; ООО «Марлин Биотех»РоссияInstitute of Gene Biology, Russian Academy of Sciences; Marlin Biotech LLCRussian FederationАкционерное общество «ГЕНЕРИУМ»РоссияGENERIUM JSCRussian Federation202420062024242Высокотехнологичные лекарственные препараты123139Copyright © Егорова Т.В., Пискунов А.А., Потеряев Д.А., 20242024Егорова Т.В., Пискунов А.А., Потеряев Д.А.Egorova T.V., Piskunov A.A., Poteryaev D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/572

ВВЕДЕНИЕ. В настоящее время генная терапия на основе аденоассоциированных вирусов (adeno-associated viruses, AAV) сталкивается с рядом барьеров биомедицинского и технологического характера, анализ и преодоление которых необходимо для дальнейшего развития данного направления генной терапии.ЦЕЛЬ. Провести анализ применения генной терапии ряда наследственных заболеваний с учетом ограничений, связанных с побочными эффектами или недостаточной эффективностью генной терапии, проблемой определения терапевтического окна и индивидуальной спецификой наследственного заболевания, а также рассмотреть подходы для снятия этих ограничений и повышения доступности генной терапии путем усовершенствования технологических подходов производства и снижения себестоимости генотерапевтических препаратов.ОБСУЖДЕНИЕ. Рассмотрен опыт применения одобренных и находящихся на этапе клинических исследований генотерапевтических препаратов. Проведена оценка применимости генной терапии на примере ряда наследственных заболеваний и показано, что правильное определение терапевтического окна препаратов и своевременная диагностика наследственных заболеваний являются критически важными для эффективной и безопасной генной терапии. Рассмотрены современные стратегии снижения риска возникновения побочных эффектов и увеличения эффективности генной терапии на основе ААV, среди которых наиболее важны следующие: поиск новых серотипов ААV, модификация капсидов и генома ААV, подавление нецелевой экспрессии с помощью микроРНК, изменение содержания CpG, поиск новых промоторов для трансгена. Проведен анализ развития технологии производства генотерапевтических препаратов на основе ААV. Наиболее перспективным представляется переход на суспензионное культивирование, усовершенствование биореакторов, применение новых методов и материалов очистки вирусных частиц, совершенствование систем трансфекции и создание новых клеточных линий-продуцентов, что в конечном счете может привести к снижению затрат на производство препаратов и повышению доступности генной терапии.ЗАКЛЮЧЕНИЕ. В настоящее время генная терапия используется только для небольшого количества наследственных заболеваний. Существенные ограничения применения генотерапевтических препаратов связаны с недостаточной эффективностью, риском возникновения побочных эффектов и высокой стоимостью лечения. Ведущиеся в настоящее время биомедицинские и технологические разработки позволят решить указанные проблемы и повысить доступность генной терапии.

INTRODICTION. Currently, gene therapy based on adeno-associated virus (AAV) vectors faces a  number of barriers, both biomedical and technological, which require studying and overcoming for further development of this gene therapy technology.AIM. This study aimed to analyse the use of gene therapy for a range of hereditary diseases, taking into account the barriers associated with its side effects and insufficient efficacy, the determination of the therapeutic window, and individual characteristics relevant to a particular hereditary disease; additionally, the study aimed to review the approaches to lifting these barriers and increasing the availability of gene therapy through the improvement of technological approaches to production and the reduction of production costs.DISCUSSION. The authors reviewed the experience accumulated for gene therapy products that were approved or undergoing clinical trials. The study included a gene therapy applicability assessment using several hereditary diseases as a case study. The assessment showed that correct determination of the therapeutic window for a medicinal product and timely diagnosis of a hereditary disease were essential for effective and safe gene therapy. The study considered the strategies used to reduce the risks of adverse events and increase the effectiveness of AAVbased gene therapy. The authors assessed technological advancements in the manufacturing of AAV-based gene therapy products. The most perspective directions were the transition to suspension culture systems, the improvement of bioreactors, the use of new methods and materials for the purification of viral particles, the improvement of transfection systems, and the creation of new host cell lines. Ultimately, this can lead to lower production costs and an increased availability of gene therapy.CONCLUSION. Currently, gene therapy is used only for a small range of hereditary diseases. Significant barriers to its use are due to insufficient efficacy, risks of adverse events, and high costs for treatment. Ongoing biomedical and technological development should lift many of these barriers and increase access to gene therapy.

генная терапиягенотерапевтический лекарственный препаратаденоассоциированный вирусААVаденоассоциированные вирусные векторынаследственные заболеваниягемофилиямиодистрофия Дюшеннаэффективность генной терапиибезопасность генной терапиитехнология производства AAVмодификация AAVтрехплазмидная технологияочистка вирусных частиц AAVgene therapygene therapy productadeno-associated virusAAVadeno-associated virus vectorshereditary diseaseshaemophiliaDuchenne muscular dystrophygene therapy efficacygene therapy safetyAAV production technologyAAV modificationtriple-plasmid transfectionAAV-particle purificationРабота выполнена без спонсорской поддержки.The study was performed without external funding.ReferencesМельникова ЕВ, Меркулов ВА, Меркулова ОВ. Генная терапия нейродегенеративных заболеваний: достижения, разработки, проблемы внедрения в клиническую практику. БИОпрепараты. 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The authors declare that there are no conflicts of interest present.