Research ArticleStem Cells

Genetic Correction of Human Induced Pluripotent Stem Cells from Patients with Spinal Muscular Atrophy

Science Translational Medicine  19 Dec 2012:
Vol. 4, Issue 165, pp. 165ra162
DOI: 10.1126/scitranslmed.3004108

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Engineering iPSC-Derived Motor Neurons for Cell Therapy

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the gene encoding the survival motor neuron 1 (SMN1) protein. The mutant protein causes loss of spinal cord motor neurons, and there is no effective therapy. Humans have a paralogous gene, SMN2, that differs from SMN1 by a single nucleotide variant within exon 7 that results in the production of an incomplete and nonfunctional protein. Now, Corti et al. investigate the feasibility of genetically engineering induced pluripotent stem cells (iPSCs) derived from SMA patients to generate motor neurons that do not show the disease phenotype. The authors generated human SMA-iPSCs using nonviral, nonintegrating episomal vectors and then performed genetic editing with oligonucleotides to modify SMN2 to produce a functional SMN1-like protein. Uncorrected SMA-iPSC–derived motor neurons reproduced disease-specific features, whereas motor neurons derived from genetically corrected SMA-iPSCs showed rescue of the disease phenotype. Upon direct transplantation into a severe SMA mouse model, corrected SMA-iPSC–derived motor neurons engrafted in the spinal cord and improved the disease phenotype. This study demonstrates the feasibility of generating patient-specific iPSCs and their motor neuron progeny that are genetically corrected and free of exogenous sequences and suggests the potential of this approach for clinical translation.