title: Stem cell-mediated transfer of a human artificial chromosome ameliorates muscular dystrophy.
abstract: In contrast to conventional gene therapy vectors, human artificial chromosomes (HACs) are episomal vectors that can carry large regions of the genome containing regulatory elements. So far, HACs have not been used as vectors in gene therapy for treating genetic disorders. Here, we report the amelioration of the dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD) using a combination of HAC-mediated gene replacement and transplantation with blood vessel-associated stem cells (mesoangioblasts). We first genetically corrected mesoangioblasts from dystrophic mdx mice with a HAC vector containing the entire (2.4 Mb) human dystrophin genetic locus. Genetically corrected mesoangioblasts engrafted robustly and gave rise to many dystrophin-positive muscle fibers and muscle satellite cells in dystrophic mice, leading to morphological and functional amelioration of the phenotype that lasted for up to 8 months after transplantation. Thus, HAC-mediated gene transfer shows efficacy in a preclinical model of DMD and offers potential for future clinical translation.
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Tedesco
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hoshiya
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Antona
authors.forename: Mattia F M
authors.initials: MF
authors.lastname: Gerli
authors.forename: Graziella
authors.initials: G
authors.lastname: Messina
authors.forename: Stefania
authors.initials: S
authors.lastname: Antonini
authors.forename: Rossana
authors.initials: R
authors.lastname: Tonlorenzi
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.forename: Libera
authors.initials: L
authors.lastname: Berghella
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
mesh_terms: D000818:Animals; D022222:Chromosomes, Artificial, Human / Q000235:genetics / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D016189:Dystrophin