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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents



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ID: 744092.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells
Authors:van der Wal, E.; Bergsma, A. J.; van Gestel, T. J. M.; In 't Groen, S. L. M.; Zaehres, H.; Arauzo-Bravo, M. J.; Scholer, H. R.; van der Ploeg, A. T.; Pijnappel, Wwmp
Date of Publication (YYYY-MM-DD):2017-06-16
Title of Journal:Mol Ther Nucleic Acids
Volume:7
Start Page:101
End Page:115
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Pompe disease is a metabolic myopathy caused by deficiency of the acid alpha-glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC)-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs.
Free Keywords:IVS1 mutation; Pompe disease; antisense oligonucleotide; exon inclusion; induced pluripotent stem cell; lysosomal storage disorder; myogenic progenitors; pre-mRNA splicing; pseudo exon; skeletal muscle differentiation
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany. Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany; Westphalian Wilhelms-University, Medical Faculty, 48149 Munster, Germany. Department of Pediatrics, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands. Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands; Department of Pediatrics, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands. Electronic address: w.pijnappel@erasmusmc.nl.
Identifiers:ISSN:2162-2531 (Print) %R 10.1016/j.omtn.2017.03.002 [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28624186 [ID No:2]
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