title: Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is among the most common genetic neurological diseases that cause infant mortality. Induced pluripotent stem cells (iPSCs) generated from skin fibroblasts from SMA patients and genetically corrected have been proposed to be useful for autologous cell therapy. We generated iPSCs from SMA patients (SMA-iPSCs) using nonviral, nonintegrating episomal vectors and used a targeted gene correction approach based on single-stranded oligonucleotides to convert the survival motor neuron 2 (SMN2) gene into an SMN1-like gene. Corrected iPSC lines contained no exogenous sequences. Motor neurons formed by differentiation of uncorrected SMA-iPSCs reproduced disease-specific features. These features were ameliorated in motor neurons derived from genetically corrected SMA-iPSCs. The different gene splicing profile in SMA-iPSC motor neurons was rescued after genetic correction. The transplantation of corrected motor neurons derived from SMA-iPSCs into an SMA mouse model extended the life span of the animals and improved the disease phenotype. These results suggest that generating genetically corrected SMA-iPSCs and differentiating them into motor neurons may provide a source of motor neurons for therapeutic transplantation for SMA.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20135, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.forename: Marianna
authors.initials: M
authors.lastname: Falcone
authors.forename: Martina
authors.initials: M
authors.lastname: Nardini
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadoni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Giorgia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Clara
authors.initials: C
authors.lastname: Bonaglia
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzo
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D017690:Cell Transplantation; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012326:RNA Splicing; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics
chemical_list: D055533:Survival of Motor Neuron 1 Protein