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

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2012 Dec 21

PMID 23253609

Citations 111

Authors

Stefania Corti

Monica Nizzardo

Chiara Simone

Marianna Falcone

Martina Nardini

Dario Ronchi

Chiara Donadoni

Sabrina Salani

Giulietta Riboldi

Francesca Magri

Giorgia Menozzi

Clara Bonaglia

Federica Rizzo

Nereo Bresolin

Giacomo P Comi

Affiliations

Soon will be listed here.

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.

Citing Articles

Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.

Pagliari E, Taiana M, Manzini P, Sali L, Quetti L, Bertolasi L Cell Mol Life Sci. 2024; 82(1):29.

PMID: 39725771 PMC: 11671459. DOI: 10.1007/s00018-024-05550-3.

Modeling riboflavin transporter deficiency type 2: from iPSC-derived motoneurons to iPSC-derived astrocytes.

Magliocca V, Lanciotti A, Ambrosini E, Travaglini L, Dezio V, DOria V Front Cell Neurosci. 2024; 18:1440555.

PMID: 39113759 PMC: 11303166. DOI: 10.3389/fncel.2024.1440555.

Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.

Grass T, Dokuzluoglu Z, Buchner F, Rosignol I, Thomas J, Caldarelli A Cell Rep Med. 2024; 5(8):101659.

PMID: 39067446 PMC: 11384962. DOI: 10.1016/j.xcrm.2024.101659.

Caspase-dependent apoptosis in Riboflavin Transporter Deficiency iPSCs and derived motor neurons.

Marioli C, Muzzi M, Colasuonno F, Fiorucci C, Cicolani N, Petrini S Cell Death Discov. 2024; 10(1):54.

PMID: 38278809 PMC: 10817897. DOI: 10.1038/s41420-024-01812-y.

Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.

Rizzo F, Bono S, Ruepp M, Salani S, Ottoboni L, Abati E Cell Mol Life Sci. 2023; 80(12):373.

PMID: 38007410 PMC: 10676309. DOI: 10.1007/s00018-023-05018-w.

References

Ebert A, Yu J, Rose Jr F, Mattis V, Lorson C, Thomson J . Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2008; 457(7227):277-80. PMC: 2659408. DOI: 10.1038/nature07677. View

Irizarry R, Hobbs B, Collin F, Beazer-Barclay Y, Antonellis K, Scherf U . Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-64. DOI: 10.1093/biostatistics/4.2.249. View

Baumer D, Lee S, Nicholson G, Davies J, Parkinson N, Murray L . Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet. 2009; 5(12):e1000773. PMC: 2787017. DOI: 10.1371/journal.pgen.1000773. View

Zhang Y, Wang D, Chen M, Yang B, Zhang F, Cao K . Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS One. 2011; 6(4):e19012. PMC: 3084251. DOI: 10.1371/journal.pone.0019012. View

Yamashita T, Kawai H, Tian F, Ohta Y, Abe K . Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain. Cell Transplant. 2010; 20(6):883-91. DOI: 10.3727/096368910X539092. View

Schmitt-John T, Drepper C, Mussmann A, Hahn P, Kuhlmann M, Thiel C . Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat Genet. 2005; 37(11):1213-5. DOI: 10.1038/ng1661. View

Crawford T, Pardo C . The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis. 1996; 3(2):97-110. DOI: 10.1006/nbdi.1996.0010. View

Passini M, Bu J, Roskelley E, Richards A, Sardi S, ORiordan C . CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J Clin Invest. 2010; 120(4):1253-64. PMC: 2846065. DOI: 10.1172/JCI41615. View

Andreassi C, Angelozzi C, Tiziano F, Vitali T, De Vincenzi E, Boninsegna A . Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet. 2003; 12(1):59-65. DOI: 10.1038/sj.ejhg.5201102. View

10.

Le T, Pham L, Butchbach M, Zhang H, Monani U, Coovert D . SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet. 2005; 14(6):845-57. DOI: 10.1093/hmg/ddi078. View

11.

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

12.

Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A . Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997; 16(3):265-9. DOI: 10.1038/ng0797-265. View

13.

Gingras M, Gagnon V, Minotti S, Durham H, Berthod F . Optimized protocols for isolation of primary motor neurons, astrocytes and microglia from embryonic mouse spinal cord. J Neurosci Methods. 2007; 163(1):111-8. DOI: 10.1016/j.jneumeth.2007.02.024. View

14.

Xiao Q, Zhao W, Beers D, Yen A, Xie W, Henkel J . Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia. J Neurochem. 2007; 102(6):2008-2019. DOI: 10.1111/j.1471-4159.2007.04677.x. View

15.

Valori C, Ning K, Wyles M, Mead R, Grierson A, Shaw P . Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med. 2010; 2(35):35ra42. DOI: 10.1126/scitranslmed.3000830. View

16.

Swarup V, Julien J . ALS pathogenesis: recent insights from genetics and mouse models. Prog Neuropsychopharmacol Biol Psychiatry. 2010; 35(2):363-9. DOI: 10.1016/j.pnpbp.2010.08.006. View

17.

Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M . A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol. 2009; 11(6):705-16. PMC: 3595613. DOI: 10.1038/ncb1876. View

18.

Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M . SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell. 2008; 133(4):585-600. PMC: 2446403. DOI: 10.1016/j.cell.2008.03.031. View

19.

Wada T, Honda M, Minami I, Tooi N, Amagai Y, Nakatsuji N . Highly efficient differentiation and enrichment of spinal motor neurons derived from human and monkey embryonic stem cells. PLoS One. 2009; 4(8):e6722. PMC: 2726947. DOI: 10.1371/journal.pone.0006722. View

20.

Schrank B, Gotz R, Gunnersen J, Ure J, Toyka K, Smith A . Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A. 1997; 94(18):9920-5. PMC: 23295. DOI: 10.1073/pnas.94.18.9920. View