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Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology
Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589062/ https://www.ncbi.nlm.nih.gov/pubmed/28629821 http://dx.doi.org/10.1016/j.ymthe.2017.05.019 |
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author | Goina, Elisa Peruzzo, Paolo Bembi, Bruno Dardis, Andrea Buratti, Emanuele |
author_facet | Goina, Elisa Peruzzo, Paolo Bembi, Bruno Dardis, Andrea Buratti, Emanuele |
author_sort | Goina, Elisa |
collection | PubMed |
description | Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII. |
format | Online Article Text |
id | pubmed-5589062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-55890622018-09-06 Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology Goina, Elisa Peruzzo, Paolo Bembi, Bruno Dardis, Andrea Buratti, Emanuele Mol Ther Original Article Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII. American Society of Gene & Cell Therapy 2017-09-06 2017-06-16 /pmc/articles/PMC5589062/ /pubmed/28629821 http://dx.doi.org/10.1016/j.ymthe.2017.05.019 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Goina, Elisa Peruzzo, Paolo Bembi, Bruno Dardis, Andrea Buratti, Emanuele Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title | Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title_full | Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title_fullStr | Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title_full_unstemmed | Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title_short | Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology |
title_sort | glycogen reduction in myotubes of late-onset pompe disease patients using antisense technology |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589062/ https://www.ncbi.nlm.nih.gov/pubmed/28629821 http://dx.doi.org/10.1016/j.ymthe.2017.05.019 |
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