Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.
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β-血红蛋白病是全球最常见的遗传性疾病。鉴于需要以谱系特异性方式大量产生血红蛋白，以及校正后的造血干细胞缺乏选择性优势，β-地中海贫血的基因治疗尤其具有挑战性。复合βE/β0 -地中海贫血是东南亚国家及其侨民中最常见的重型地中海贫血形式。βE -珠蛋白等位基因存在一个点突变，导致选择性剪接。异常剪接形式是非编码的，而正确剪接的信使RNA表达一种部分不稳定的突变βE -珠蛋白。当这种情况与无功能的β0等位基因相结合时，会导致β-珠蛋白合成大幅减少，大约一半的βE/β0 -地中海贫血患者依赖输血。唯一可用的治愈性疗法是同种异体造血干细胞移植，尽管大多数患者没有人类白细胞抗原匹配、基因相同的供体，而且即使有供体的患者仍面临排斥反应或移植物抗宿主病的风险。在此我们表明，在慢病毒β-珠蛋白基因转移33个月后，一名自幼年早期就依赖每月输血的重型βE/β0 -地中海贫血成年患者在过去21个月中已不再依赖输血。血液血红蛋白维持在9 - 10 g/dl之间，其中三分之一包含载体编码的β-珠蛋白。大部分治疗益处来自一个占优势的、偏向髓系的细胞克隆，在该克隆中，整合的载体导致红系细胞中HMGA2的转录激活，并且一种对let - 7微小RNA降解不敏感的截短HMGA2 mRNA的表达进一步增加。伴随治疗效果出现的克隆优势可能是偶然的和随机的，或者是由于干细胞/祖细胞中HMGA2基因失调导致的迄今为止良性的细胞扩增所致。
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 diasporas. 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 instability. 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-dependent. 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 trans-fusion 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 stochasticor resultfrom a hithertobenign cellexpansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.
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DOI：
10.1073/pnas.0711666105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Miccio, Annarita;Cesari, Rossano;Ferrari, Giuliana
通讯作者：
Ferrari, Giuliana
影响因子：
20.3
作者：
Hanawa, H;Hargrove, PW;Persons, DA
通讯作者：
Persons, DA
影响因子：
12.4
作者：
Hanawa, Hideki;Yamamoto, Motoko;Persons, Derek A.
通讯作者：
Persons, Derek A.
影响因子：
23.9
作者：
Dykstra, Brad;Kent, David;Eaves, Connie
通讯作者：
Eaves, Connie
影响因子：
20.3
作者：
Inoue, Norimitsu;Izui-Sarumaru, Tomohisa;Kinoshita, Taroh
通讯作者：
Kinoshita, Taroh