Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute12056010.23868/gc120560ArticlesСтатьиReview ArticleSite-specific genome editing for hematopoetic stem cells transplantation-based gene therapy approachesГЕННАЯ ТЕРАПИЯ НА ОСНОВЕ ТРАНСПЛАНТАЦИИ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК С ИСПОЛЬЗОВАНИЕМ САЙТ-СПЕЦИФИЧЕСКОГО РЕДАКТИРОВАНИЯ ГЕНОМАLepikK. VЛепикК. ВPopovaM. OПоповаМО. Omarina.popova.spb@gmail.comShakirovaA. IШакироваА. ИSergeevV. SСергеевВ. СPotterA. YПоттерА. ЯBarkhatovI. MБархатовИ. МFehseB.ФезеБ.AfanasyevB. VАфанасьевБ. ВR.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and TransplantationНаучно-Исследовательский институт детской онкологии, гематологии и трансплантологии им. Р.М. ГорбачевойUniversity Medical Center (UKE] Hamburg-EppendorfГамбургский Университет15062016112VOL 11, NO2 (2016)ТОМ 11, №2 (2016)213105012023Copyright ©; 2016, Eco-VectorCopyright ©; 2016, Эко-Вектор2016Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/120560

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole universal curative approach for a number of hereditary diseases, such as severe combined immunodeficiency (SCID), severe non-SCID primary immunodeficiencies (non-SCID PID), hematologic diseases and part of lysosomal storage disorders. Unfortunately, to date, HSCT remains a high-risk procedure, especially in cases of poor performance status of the patient and lack of HLA-matched related donors. In those cases the correction of the patients autologous HSCs with gene therapy could be a promising alternative. Current paradigm of HSCT-based gene therapy approaches is based on the utilization of viral vectors, which may lead to the severe complications due to insertion mutagenesis. Throughout the last several years, new technologies of site-specific genome editing with endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 were introduced. These enzymes may induce a DNA doublestranded break, homology-directed repair and insertion of functional copy of gene in precisely targeted locus. This review focuses on the advantages and disadvantages of the genome editing tools utilization that carries the great potential of changing the paradigm of gene therapy in the setting of HSCT.

Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) остается единственным универсальным методом, позволяющим добиться излечения ряда наследственных заболеваний, таких как первичные иммунодефициты (ПИД), в том числе тяжелые комбинированные иммунодефициты (ТКИН), гемоглобинопатии и другие гематологические и моногенные заболевания. Однако процедура алло-ТГСК сопряжена с высоким риском развития тяжелых осложнений, особенно в случае отсутствия HLA-совместимого родственного донора и снижения соматического статуса больного на момент трансплантации. Альтернативным подходом является исправление генетического дефекта в аутогенных ГСК пациента при помощи методов генной терапии. Существующая парадигма генной терапии ГСК включает использование вирусного переноса функциональной копии гена, что сопряжено с риском тяжелых осложнений, связанных с инсерционным мутагенезом. В последние годы были разработаны технологии сайт-специфического редактирования генома с использованием рекомбинантных эндонуклеаз, таких как ZFN, TALEN и CRISPR/Cas9, способных инициировать двухцепочечные разрывы ДНК и интеграцию функциональной копии гена в строго определенном целевом локусе генома. Данный обзор посвящен достижениям и проблемам подходов генной терапии с использованием инструментов сайт-специфического редактирования генома на основе трансплантации гемопоэтических стволовых клеток.

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