Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/6459 |
Resumo: | Lysosomal Storage Disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undegraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there is currently a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes. GlcNAc-1-phosphotransferase is a multimeric enzyme complex encoded by two genes: GNPTAB and GNPTG. One of the most frequent ML II causal mutation is a dinucleotide deletion on exon 19 of GNPTAB (c.3503_3504del) that leads to the generation of a truncated protein, loss of GlcNAc-1-phosphotransferase activity, and missorting of multiple lysosomal enzymes. Presently, there is no therapy available for ML II. In this study we explored the possibility of an innovative therapeutic strategy for ML II based on the use of antisense oligonucleotides (AOs) capable to induce the skipping of GNPTAB exon 19 harboring the most common disease-causing mutation, c.3503_3504del. The approach confirmed the ability of specific AOs for RNA splicing modulation, thus paving the way for future studies on the therapeutic potential of this strategy. |
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Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA levelAntisense oligonucleotide therapy for ML IILysosomal Storage DisordersMetabolic DiseasesMucolipidosis Type IISplicing MutationsGNPTAB geneAntisense TherapyDoenças GenéticasDoenças Lisossomais de SobrecargaLysosomal Storage Disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undegraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there is currently a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes. GlcNAc-1-phosphotransferase is a multimeric enzyme complex encoded by two genes: GNPTAB and GNPTG. One of the most frequent ML II causal mutation is a dinucleotide deletion on exon 19 of GNPTAB (c.3503_3504del) that leads to the generation of a truncated protein, loss of GlcNAc-1-phosphotransferase activity, and missorting of multiple lysosomal enzymes. Presently, there is no therapy available for ML II. In this study we explored the possibility of an innovative therapeutic strategy for ML II based on the use of antisense oligonucleotides (AOs) capable to induce the skipping of GNPTAB exon 19 harboring the most common disease-causing mutation, c.3503_3504del. The approach confirmed the ability of specific AOs for RNA splicing modulation, thus paving the way for future studies on the therapeutic potential of this strategy.This work was financially supported by Fundação para a Ciência e Tecnologia (FCT) IP (project: PTDC /BBBBMD/6301/2014); and Asociación Nour de Mucolipidosis (project: Skip 19).Mary Ann LiebertRepositório Científico do Instituto Nacional de SaúdeMatos, LilianaVilela, ReginaRocha, MelissaSantos, Juliana InêsCoutinho, Maria FranciscaGaspar, PauloPrata, Maria JoãoAlves, Sandra2021-04-13T00:30:14Z2020-04-132020-04-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/6459engHum Gene Ther. 2020 Apr 13. Epub 2020 Apr 13. doi: 10.1089/hum.2020.0341043-034210.1089/hum.2020.034info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:41:44Zoai:repositorio.insa.pt:10400.18/6459Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:41:36.104453Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level Antisense oligonucleotide therapy for ML II |
title |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
spellingShingle |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level Matos, Liliana Lysosomal Storage Disorders Metabolic Diseases Mucolipidosis Type II Splicing Mutations GNPTAB gene Antisense Therapy Doenças Genéticas Doenças Lisossomais de Sobrecarga |
title_short |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
title_full |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
title_fullStr |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
title_full_unstemmed |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
title_sort |
Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level |
author |
Matos, Liliana |
author_facet |
Matos, Liliana Vilela, Regina Rocha, Melissa Santos, Juliana Inês Coutinho, Maria Francisca Gaspar, Paulo Prata, Maria João Alves, Sandra |
author_role |
author |
author2 |
Vilela, Regina Rocha, Melissa Santos, Juliana Inês Coutinho, Maria Francisca Gaspar, Paulo Prata, Maria João Alves, Sandra |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Matos, Liliana Vilela, Regina Rocha, Melissa Santos, Juliana Inês Coutinho, Maria Francisca Gaspar, Paulo Prata, Maria João Alves, Sandra |
dc.subject.por.fl_str_mv |
Lysosomal Storage Disorders Metabolic Diseases Mucolipidosis Type II Splicing Mutations GNPTAB gene Antisense Therapy Doenças Genéticas Doenças Lisossomais de Sobrecarga |
topic |
Lysosomal Storage Disorders Metabolic Diseases Mucolipidosis Type II Splicing Mutations GNPTAB gene Antisense Therapy Doenças Genéticas Doenças Lisossomais de Sobrecarga |
description |
Lysosomal Storage Disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undegraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there is currently a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes. GlcNAc-1-phosphotransferase is a multimeric enzyme complex encoded by two genes: GNPTAB and GNPTG. One of the most frequent ML II causal mutation is a dinucleotide deletion on exon 19 of GNPTAB (c.3503_3504del) that leads to the generation of a truncated protein, loss of GlcNAc-1-phosphotransferase activity, and missorting of multiple lysosomal enzymes. Presently, there is no therapy available for ML II. In this study we explored the possibility of an innovative therapeutic strategy for ML II based on the use of antisense oligonucleotides (AOs) capable to induce the skipping of GNPTAB exon 19 harboring the most common disease-causing mutation, c.3503_3504del. The approach confirmed the ability of specific AOs for RNA splicing modulation, thus paving the way for future studies on the therapeutic potential of this strategy. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-04-13 2020-04-13T00:00:00Z 2021-04-13T00:30:14Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/6459 |
url |
http://hdl.handle.net/10400.18/6459 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Hum Gene Ther. 2020 Apr 13. Epub 2020 Apr 13. doi: 10.1089/hum.2020.034 1043-0342 10.1089/hum.2020.034 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Mary Ann Liebert |
publisher.none.fl_str_mv |
Mary Ann Liebert |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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