人体试验疗效达100%!NEJM发布基因治疗突破成果
2018/04/20
自从人类开始基因组计划之后,科学家们一直希望有一天可以通过编辑修饰患者的致病基因从根本上治愈疾病。现在,一个国际临床研究小组取得了初步的成功,他们使用基因疗法治疗输血依赖型β-地中海贫血,1-2期临床试验取得100%疗效。


doi:10.1038/nature09328

研究结果于2010年以题为“Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia”发表在《自然》杂志上。

输血依赖型β-地中海贫血患者基因治疗

如今,这个国际化研究小组再次合作,进一步改进了试验(主要是病毒载体方面的改进),阶段性结果于2018年4月19日以题为“Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia”发表在《新英格兰医学杂志》上。


DOI: 10.1056/NEJMoa1705342

在预先确定了β-珠蛋白(βA-T87Q)基因的慢病毒载体可替代β地中海贫血患者的长期红细胞输注后,Leboulch希望评估这种基因疗法对输血依赖性β地中海贫血患者的安全性和有效性。

“我们一直希望我们的研究成果能让病人受益,” Leboulch说, “我们已经通过临床前模型以及原理验证阶段的工作,现在可以评估其对这种疾病患者的有效性。”

在新发表NEJM的研究中,Leboulch、Cavazzana及其同事与国际临床研究人员合作,纳入22位输血依赖型地中海贫血患者(12-35岁),治疗地点分布在美国、泰国和法国。

具体来说,在两个1-2期研究中,研究人员从他们身上获得了转导自体CD34+细胞,并用编码成人血红蛋白(HbA)的LentiGlobin BB305载体在体外转导细胞。然后在患者进行清髓预处理后再将细胞回输。

结果发现,输注基因修饰细胞后,13名非β-globin完全缺失(β0/β0表型)患者都停止接受红细胞输血。9例β0/β0表型或IVS1-110突变两个拷贝的患者,年平均输血量减少73%,3例患者中止输注红细胞。而且,没有与药物产品相关的严重不良事件。

Leboulch表示,“在大量病人的多中心试验中,我们看到试验结果的一致性。当然这种治疗方法还有改进的余地,我们希望看到,即便是最严重的疾病患者,也能消除其对输血的依赖。

责编:浮苏

参考资料

Gene therapy for beta-thalassemia safe, effective in people

NEJM:基因治疗地中海贫血1-2期临床试验取得100%疗效

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  • Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

    The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.

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  • Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia

    BACKGROUND Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia. METHODS In two phase 1–2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. RESULTS At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non–β0/β0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526.)

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