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


ABSTRACT: 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.

SUBMITTER: Paulis M 

PROVIDER: S-EPMC7029378 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Paulis Marianna M   Susani Lucia L   Castelli Alessandra A   Suzuki Teruhiko T   Hara Takahiko T   Straniero Letizia L   Duga Stefano S   Strina Dario D   Mantero Stefano S   Caldana Elena E   Sergi Lucia Sergi LS   Villa Anna A   Vezzoni Paolo P  

Molecular therapy. Methods & clinical development 20200121


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-establishe  ...[more]

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