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Chromosome Transplantation: A Possible Approach to Treat Human X-linked Disorders.
Molecular Therapy - Methods & Clinical Development ( IF 4.7 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.omtm.2020.01.003
Marianna Paulis 1, 2 , Lucia Susani 1, 2 , Alessandra Castelli 1, 2 , Teruhiko Suzuki 3 , Takahiko Hara 3 , Letizia Straniero 4 , Stefano Duga 2, 4 , Dario Strina 1, 2 , Stefano Mantero 1, 2 , Elena Caldana 1, 2 , Lucia Sergi Sergi 5 , Anna Villa 1, 5 , Paolo Vezzoni 1, 2
Affiliation  

Many human genetic diseases are associated with gross mutations such as aneuploidies, deletions, duplications, or inversions. For these "structural" disorders, conventional gene therapy, based on viral vectors and/or on programmable nuclease-mediated homologous recombination, is still unsatisfactory. To correct such disorders, chromosome transplantation (CT), defined as the perfect substitution of an endogenous defective chromosome with an exogenous normal one, could be applied. CT re-establishes a normal diploid cell, leaving no marker of the procedure, as we have recently shown in mouse pluripotent stem cells. To prove the feasibility of the CT approach in human cells, we used human induced pluripotent stem cells (hiPSCs) reprogrammed from Lesch-Nyhan (LN) disease patients, taking advantage of their mutation in the X-linked HPRT gene, making the LN cells selectable and distinguishable from the resistant corrected normal cells. In this study, we demonstrate, for the first time, that CT is feasible in hiPSCs: the normal exogenous X chromosome was first transferred using an improved chromosome transfer system, and the extra sex chromosome was spontaneously lost. These CT cells were functionally corrected and maintained their pluripotency and differentiation capability. By inactivation of the autologous HPRT gene, CT paves the way to the correction of hiPSCs from several X-linked disorders.

中文翻译:

染色体移植:一种治疗人类X连锁疾病的可能方法。

许多人类遗传疾病都与诸如非整倍性,缺失,重复或倒位等重大突变相关。对于这些“结构性”疾病,基于病毒载体和/或基于可编程核酸酶介导的同源重组的常规基因疗法仍然不能令人满意。为了纠正这种疾病,可以应用染色体移植(CT),将其定义为用外源正常染色体完美替代内源性缺陷染色体。正如我们最近在小鼠多能干细胞中所显示的,CT重新建立了正常的二倍体细胞,没有留下该过程的标记。为了证明CT法在人细胞中的可行性,我们利用从Lesch-Nyhan(LN)疾病患者中重新编程的人诱导多能干细胞(hiPSC),利用了它们在X连锁HPRT基因中的突变,使LN细胞与抗性校正的正常细胞具有选择性和区别性。在这项研究中,我们首次证明CT在hiPSC中是可行的:正常的外源X染色体首先使用改良的染色体转移系统转移,而多余的性染色体自发丢失。这些CT细胞经过功能校正,并保持其多能性和分化能力。通过使自体HPRT基因失活,CT为纠正来自几种X连锁疾病的hiPSC铺平了道路。并且多余的性染色体自发地丢失了。这些CT细胞经过功能校正,并保持其多能性和分化能力。通过使自体HPRT基因失活,CT为纠正来自几种X连锁疾病的hiPSC铺平了道路。并且多余的性染色体自发地丢失了。这些CT细胞经过功能校正,并保持其多能性和分化能力。通过使自体HPRT基因失活,CT为纠正来自几种X连锁疾病的hiPSC铺平了道路。
更新日期:2020-01-21
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