TY - JOUR
T1 - Chromosome Transplantation
T2 - A Possible Approach to Treat Human X-linked Disorders
AU - Paulis, Marianna
AU - Susani, Lucia
AU - Castelli, Alessandra
AU - Suzuki, Teruhiko
AU - Hara, Takahiko
AU - Straniero, Letizia
AU - Duga, Stefano
AU - Strina, Dario
AU - Mantero, Stefano
AU - Caldana, Elena
AU - Sergi, Lucia Sergi
AU - Villa, Anna
AU - Vezzoni, Paolo
N1 - Funding Information:
The research leading to these results has received funding from the PNR-CNR Aging Program 2012–2014 to P.V. A.C. is the recipient of a fellowship from Fondazione Nicola del Roscio .
Publisher Copyright:
© 2020 The Author(s)
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/12
Y1 - 2020/6/12
N2 - 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.
AB - 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.
KW - chromosome transfer
KW - chromosome transplantation
KW - genetic therapy
KW - genomic disorders
KW - induced pluripotent stem cells
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U2 - 10.1016/j.omtm.2020.01.003
DO - 10.1016/j.omtm.2020.01.003
M3 - Article
AN - SCOPUS:85079377715
VL - 17
SP - 369
EP - 377
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
SN - 2329-0501
ER -