Chromosome transplantation as a novel approach for correcting complex genomic disorders

// Marianna Paulis 1,2 , Alessandra Castelli 1,2 , Lucia Susani 1,2 , Michela Lizier 2,3 , Irina Lagutina 4 , Maria Luisa Focarelli 1,2 , Camilla Recordati 5 , Paolo Uva 6 , Francesca Faggioli 1,2 , Tui Neri 1,2 , Eugenio Scanziani 5,7 , Cesare Galli 4,8 , Franco Lucchini 3 , Anna Villa 1,2,* and Paolo Vezzoni 1,2,* 1 Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan, Italy 2 Humanitas Clinical and Research Center, Rozzano, Milan, Italy 3 Centro Ricerche Biotecnologiche, Universita Cattolica del Sacro Cuore, Cremona, Italy 4 Avantea, Cremona, Italy 5 Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy 6 CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Cagliari, Italy 7 Department of Veterinary Sciences and Public Health, University of Milan, Milan, Italy 8 Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Bologna, Italy * These authors jointly supervised this work Correspondence to: Paolo Vezzoni, email: // Marianna Paulis, email: // Keywords : embryonic stem cells, chromosome transplantation, microcell fusion, genomic disorders, cell therapy Received : September 28, 2015 Accepted : October 01, 2015 Published : October 17, 2015 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.