Mansilla-Soto Jorge, Rivière Isabelle, Sadelain Michel
Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Br J Haematol. 2011 Sep;154(6):715-27. doi: 10.1111/j.1365-2141.2011.08773.x. Epub 2011 Jun 28.
Sickle cell anaemia is a severe inherited blood disorder for which there is presently no curative therapy other than allogeneic haematopoietic stem cell (HSC) transplantation. This therapeutic option, however, is not available to most patients because of the lack of a matched related donor. Different genetic strategies aiming to treat the anaemia and prevent sickling are under investigation. They include strategies to transfer a regulated globin gene in autologous HSCs-the most developed approach, which is about to undergo clinical evaluation-, and strategies to either restore endogenous HBG expression, repair or eliminate HBB(S) mutant transcripts, or correct the sickle mutation in HSCs or induced pluripotent stem cells. Their common ultimate goals are to afford therapeutic levels of HbA or HbF in the erythroid progeny of autologous HSCs (sufficient to prevent pathological sickling) and engraft the genetically modified HSCs with minimal short-term toxicity (primarily caused by the conditioning regimen) and long-term toxicity (primarily caused by genotoxicity). We discuss here the status of application of these technologies, outlining recent advances and the hurdles that lay ahead.
镰状细胞贫血是一种严重的遗传性血液疾病，目前除了异基因造血干细胞（HSC）移植外没有治愈疗法。然而，由于缺乏匹配的相关供体，大多数患者无法获得这种治疗选择。旨在治疗贫血和预防镰变的不同基因策略正在研究中。这些策略包括在自体造血干细胞中转移一个受调控的珠蛋白基因的策略——这是最成熟的方法，即将进行临床评估——以及恢复内源性HBG表达、修复或消除HBB(S)突变转录本，或纠正造血干细胞或诱导多能干细胞中的镰状突变的策略。它们共同的最终目标是在自体造血干细胞的红系后代中提供治疗水平的HbA或HbF（足以防止病理性镰变），并使基因修饰的造血干细胞以最小的短期毒性（主要由预处理方案引起）和长期毒性（主要由基因毒性引起）植入。我们在此讨论这些技术的应用现状，概述近期进展和未来面临的障碍。
