Chromosome Transplantation: A Possible Approach to Treat Human X-linked Disorders

Molecular Therapy: Methods & Clinical Development

Lucia Sergi Sergi¹  Teruhiko Suzuki²  Paolo Vezzoni²  Lucia Susani²  Letizia Straniero²  Stefano Mantero³  Elena Caldana⁴  Marianna Paulis⁵  Alessandra Castelli⁵  Takahiko Hara⁵  Anna Villa⁵  Stefano Duga⁶  Dario Strina⁶ 

[1] Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy;Humanitas Clinical and Research Center, Rozzano (MI), Italy;Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy;Humanitas Clinical and Research Center, Rozzano (MI), Italy;National Research Council (CNR)-IRGB/UOS, Milan, Italy;Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;

关键词: genomic disorders;    induced pluripotent stem cells;    genetic therapy;    chromosome transfer;    chromosome transplantation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown