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.

Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy / S. Corti, M. Nizzardo, C. Simone, M. Falcone, M. Nardini, D. Ronchi, C. Donadoni, S. Salani, G. Riboldi, F. Magri, G. Menozzi, C. Bonaglia, F. Rizzo, N. Bresolin, G.P. Comi. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 4:165(2012 Dec 19), pp. 165ra162.1-165ra162.17. [10.1126/scitranslmed.3004108]

Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy

S. Corti;M. Nizzardo;C. Simone;D. Ronchi;F. Magri;F. Rizzo;N. Bresolin;G. P. Comi
2012-12-19

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.
Pluripotent Stem Cells; Survival of Motor Neuron 1 Protein; Muscular Atrophy, Spinal; RNA Splicing; Humans; Genetic Vectors; Gene Expression; Genetic Therapy; Cell Transplantation; Motor Neurons
Settore MED/26 - Neurologia
Settore MED/50 - Scienze Tecniche Mediche Applicate
Settore BIO/05 - Zoologia
Settore MED/03 - Genetica Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/220493
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