Abstract
Advances in ex vivo technologies of human genome editing have made it possible to develop new approaches to the treatment of genetic, oncological, infectious and other diseases, which may involve the use of biomedical cell products. However, despite the rapid development of these technologies and a large number of clinical trials conducted in many countries around the world, only 4 products (Strimvelis, Zalmoxis, Kymriah and Yescarta) containing ex vivo genetically modified human cells are authorised for use in the European Union and the United States of America. This paper considers three promising technologies (ZFN, TALEN and CRISPR) that allow for easy and effective editing of the genome at the sites of interest, thereby creating a platform for further development of the genetic engineering of human cells. It describes the technology of engineering chimeric antigen receptors (CARs). It also provides data on the efficacy and safety of the approved products: Strimvelis which contains autologous CD34+ cells transduced ex vivo with a retroviral vector containing adenosine deaminase gene, Zalmoxis which contains modified allogeneic T-cells, and two products: Kymriah and Yescarta which contain autologous T-cells with CARs to CD19 antigen, intended for the treatment of CD19+ hematological malignancies.
Highlights
Advances in ex vivo technologies of human genome editing have made it possible to develop new approaches to the treatment of genetic, oncological, infectious and other diseases, which may involve the use of biomedical cell products
Despite the rapid development of these technologies and a large number of clinical trials conducted in many countries around the world, only 4 products (Strimvelis, Zalmoxis, Kymriah and Yescarta) containing ex vivo genetically modified human cells are authorised for use in the European Union and the United States of America
This paper considers three promising technologies (ZFN, TALEN and CRISPR) that allow for easy and effective editing of the genome at the sites of interest, thereby creating a platform for further development of the genetic engineering of human cells
Summary
Для успешного редактирования генома необходимо введение сайт-специфического двухцепочечного разрыва ДНК, который репарируется клеткой с помощью гомологичной рекомбинации или негомологичным соединением концов. В отличие от ZFN и TALEN, при использовании которых для каждого проекта необходимо создание сложных конструкций ДНК-связывающих доменов и нуклеазы FokI, система CRISPR Каждый домен TALE распознает один нуклеотид, FokI при димеризации вызывает двухцепочечный разрыв ДНК; В — CRISPR/Cas. Восстановление иммунитета вызвано необходимостью снижения заболеваемости бактериальными, грибковыми и вирусными инфекциями пациентов после гаплоТГСК, так как полная регенерация Ти В-клеток происходит в течение 2 лет (в зависимости от возраста и предшествующего лечения), также на восстановление влияет иммуносупрессивная терапия для профилактики реакции «трансплантат против хозяина» (РТПХ) [34, 35]. Количество инфекционных заболеваний было ниже у пациентов с восстановленным иммунитетом (n = 23) по сравнению с пациентами, у которых не было зарегистрировано восстановление иммунитета (n = 7), что также приводило к снижению смертности — 17 и 71 % соответственно [33, 37].
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