Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII.
Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII.
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非生物毒性调节促进了使用生物工程因子VIII进行血友病A的造血干细胞基因治疗。
DOI：
10.1016/j.omtm.2021.04.016
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发表时间：
2021-06-11
期刊：
影响因子：
--
通讯作者：
Doering CB
中科院分区：
文献类型：
--
作者：
Russell AL;Prince C;Lundgren TS;Knight KA;Denning G;Alexander JS;Zoine JT;Spencer HT;Chandrakasan S;Doering CB
造血干细胞和祖细胞（HSPC）慢病毒基因治疗是一种有前途的终身治愈血友病A（HA）的策略。与这种方法相关的主要风险集中在需要进行移植前预处理，以便分别为干细胞和凝血因子VIII留出空间并提供免疫抑制。传统的调理剂利用遗传毒性作用机制，如DNA烷基化，增加不育、感染和继发性恶性肿瘤的风险。在目前的研究中，我们描述了一种非遗传毒性的空调协议，使用免疫毒素靶向CD 117（c-kit），以实现内源性造血干细胞耗竭和鸡尾酒的单克隆抗体，以提供短暂的免疫抑制转基因产品在小鼠HA基因治疗模型。该策略提供了使用编码生物工程高表达因子VIII变体（称为ET 3）的重组慢病毒载体（LV）离体遗传修饰的造血干细胞的高水平植入。因子VIII促凝血活性水平持续升高至正常范围，并实现表型校正。此外，未观察到免疫排斥或抗ET 3免疫的发展。这些临床前数据支持HA HSPC LV基因治疗中基于非遗传毒性抗体的预处理的临床转化。Doering及其同事开发了一种无遗传毒性的预处理方案，该方案允许用高表达因子VIII变体遗传修饰的造血干细胞和祖细胞在血友病A小鼠中成功长期植入。通过非遗传毒性造血干细胞移植基因治疗实现了持久的因子VIII表达和止血校正。
Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA. Doering and colleagues develop a non-genotoxic conditioning regimen that permits successful long-term engraftment of hematopoietic stem and progenitor cells genetically modified with a high-expression factor VIII variant in hemophilia A mice. Durable factor VIII expression and hemostatic correction are achieved through non-genotoxic hematopoietic stem cell transplantation gene therapy.
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影响因子：
17.1
作者：
Chhabra A;Ring AM;Weiskopf K;Schnorr PJ;Gordon S;Le AC;Kwon HS;Ring NG;Volkmer J;Ho PY;Tseng S;Weissman IL;Shizuru JA
通讯作者：
Shizuru JA
DOI：
10.1097/mbc.0000000000000571
发表时间：
2016-12
期刊：
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis
影响因子：
--
作者：
Auerswald G;Dolan G;Duffy A;Hermans C;Jiménez-Yuste V;Ljung R;Morfini M;Lambert T;Šalek SZ
通讯作者：
Šalek SZ
影响因子：
4.3
作者：
Bacigalupo, Andrea;Ballen, Karen;Rizzo, Doug;Giralt, Sergio;Lazarus, Hillard;Ho, Vincent;Apperley, Jane;Slavin, Shimon;Pasquini, Marcelo;Sandmaier, Brenda M.;Barrett, John;Blaise, Didier;Lowski, Robert;Horowitz, Mary
通讯作者：
Horowitz, Mary
影响因子：
2.6
作者：
Bazinet, A.;Popradi, G.
通讯作者：
Popradi, G.
DOI：
10.1182/asheducation-2014.1.461
发表时间：
2014-12-01
影响因子：
3
作者：
Doering, Christopher B.;Spencer, H. Trent
通讯作者：
Spencer, H. Trent