Abstract
Genomic disorders resulting from large rearrangements of the genome remain an important unsolved issue in gene therapy. Chromosome transplantation, defined as the perfect replacement of an endogenous chromosome with a homologous one, has the potential of curing this kind of disorders. Here we report the first successful case of chromosome transplantation by replacement of an endogenous X chromosome carrying a mutation in the Hprt genewith a normal one in mouse embryonic stem cells (ESCs), correcting the genetic defect. The defect was also corrected by replacing the Y chromosome with an X chromosome. Chromosome transplanted clones maintained in vitro and in vivo features of stemness and contributed to chimera formation. Genome integrity was confirmed by cytogenetic and molecular genome analysis. The approach here proposed, with some modifications, might be used to cure various disorders due to other X chromosome aberrations in induced pluripotent stem (iPS) cells derived from affected patients.
Highlights
The hope of correcting genetic diseases has been around for long time, since the first gene transfer to cultured cells was documented [1]
An exogenous normal mouse X chromosome (Hprt+) was transferred through Microcell mediated chromosome transfer (MMCT) into recipient male mouse embryonic stem cells (ESCs) carrying a mutation in the Hprt gene (Hprt-)
Clones in which an endogenous sex chromosome has been lost were identified from the initial pool; these clones could become either transplanted XY, resulting from loss of the endogenous X chromosome, or, alternatively, substituted XX resulting from loss of the endogenous Y chromosome
Summary
The hope of correcting genetic diseases has been around for long time, since the first gene transfer to cultured cells was documented [1]. Very simple in theory, gene therapy has met both expected and unexpected difficulties, regarding inefficient gene transfer, random integration, silencing of the transferred gene and difficult expansion and differentiation of the specific cell types needed to rescue the phenotype. These limits apply to essentially any genetic disease to be studied. We refer here to those that can be listed as “genomic disorders” [2], which apparently could neither be treated with conventional techniques such as viral vectors, nor are likely to be treated with the homologous recombination strategy. Any new approach aimed at solving the www.impactjournals.com/oncotarget specific hurdles presented by these genomic disorders will be of interest
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
