Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease.
Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease.
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DOI：
10.1126/scitranslmed.abf2444
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发表时间：
2021-06-16
影响因子：
17.1
通讯作者：
Porteus MH
中科院分区：
文献类型：
--
作者：
Lattanzi A;Camarena J;Lahiri P;Segal H;Srifa W;Vakulskas CA;Frock RL;Kenrick J;Lee C;Talbott N;Skowronski J;Cromer MK;Charlesworth CT;Bak RO;Mantri S;Bao G;DiGiusto D;Tisdale J;Wright JF;Bhatia N;Roncarolo MG;Dever DP;Porteus MH
镰状细胞病（SCD）是最常见的单基因严重疾病，全世界每年有30万新生儿。SCD是由β-珠蛋白基因（HBB）第六密码子中的单点突变导致的常染色体隐性遗传，导致镰状血红蛋白。自体造血干/祖细胞（HSPCs）的β-珠蛋白基因校正可能是治疗SCD的理想方法。我们之前开发了一种HBB基因靶向策略，该策略利用高保真Cas9与化学修饰的指导RNA预复合，以诱导HSPC中SCD引起突变的rAAV 6介导的基因校正。在此，我们提供了基础翻译数据，证明了在来自健康和SCD患者供体的普乐沙福动员的CD 34+细胞中进行HBB基因校正的临床前可行性、疗效和毒理学（制剂-gcHBB-SCD）。值得注意的是，我们在临床规模的gcHBB-SCD生产和免疫缺陷NSG小鼠的长期植入中实现了高达60%的HBB等位基因校正，多个造血器官中的多谱系等位基因基因校正频率为20%。长期安全性致瘤性/毒理学研究表明，植入的gcHBB-SCD制剂无异常造血、遗传毒性或致瘤性证据。总之，该临床前数据支持用于启动SCD患者I/II期临床试验的基因校正策略的安全性、有效性和再现性。临床前有效性和安全性数据支持启动患者源性造血干细胞中β-珠蛋白基因校正治疗镰状细胞病的I/II期临床试验。
Sickle cell disease (SCD) is the most common monogenic serious disease with 300,000 births annually worldwide. SCD is autosomal recessive from a single point mutation in codon six of the β-globin gene (HBB) resulting in sickle hemoglobin. Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) might be an ideal treatment of SCD. We previously developed an HBB gene targeting strategy that utilizes high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce rAAV6-mediated gene correction of the SCD-causing mutation in HSPCs. Here we present foundational translational data that demonstrate the pre-clinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (Drug Product-gcHBB-SCD). Notably, we achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing and long-term engraftment in immunodeficient NSG mice, with multi-lineage allele gene correction frequencies of 20% in multiple hematopoietic organs. The long-term safety tumorigenicity/toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity or tumorigenicity from the engrafted gcHBB-SCD Drug Product. Altogether, this preclinical data supports the safety, efficacy, and reproducibility of a gene correction strategy for initiation of a Phase I/II clinical trial for SCD patients. The pre-clinical efficacy and safety data support the initiation of a phase I/II clinical trial for β-globin gene correction in patient-derived hematopoietic stem cells for the treatment of sickle cell disease.
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影响因子：
3.7
作者：
Chagraoui, Jalila;Lehnertz, Bernhard;Sauvageau, Guy
通讯作者：
Sauvageau, Guy
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Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
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Naldini, Luigi
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14.8
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Bak RO;Dever DP;Porteus MH
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Porteus MH
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Hendel A;Bak RO;Clark JT;Kennedy AB;Ryan DE;Roy S;Steinfeld I;Lunstad BD;Kaiser RJ;Wilkens AB;Bacchetta R;Tsalenko A;Dellinger D;Bruhn L;Porteus MH
通讯作者：
Porteus MH
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
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van Steensel B