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Development of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA level

2020-04-13Journal article Restricted access
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dc.contributor.authorMatos, Liliana
dc.contributor.authorVilela, Regina
dc.contributor.authorRocha, Melissa
dc.contributor.authorSantos, Juliana Inês
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorGaspar, Paulo
dc.contributor.authorPrata, Maria João
dc.contributor.authorAlves, Sandra
dc.date.accessioned2020-04-20T10:56:35Z
dc.date.available2021-04-13T00:30:14Z
dc.date.issued2020-04-13
dc.description.abstractLysosomal 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.pt_PT
dc.description.sponsorshipThis 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).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Gene Ther. 2020 Apr 13. Epub 2020 Apr 13. doi: 10.1089/hum.2020.034pt_PT
dc.identifier.doi10.1089/hum.2020.034pt_PT
dc.identifier.issn1043-0342
dc.identifier.urihttp://hdl.handle.net/10400.18/6459
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMary Ann Liebertpt_PT
dc.relation.publisherversionhttps://www.liebertpub.com/doi/10.1089/hum.2020.034pt_PT
dc.subjectLysosomal Storage Disorderspt_PT
dc.subjectMetabolic Diseasespt_PT
dc.subjectMucolipidosis Type IIpt_PT
dc.subjectSplicing Mutationspt_PT
dc.subjectGNPTAB genept_PT
dc.subjectAntisense Therapypt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectDoenças Lisossomais de Sobrecargapt_PT
dc.titleDevelopment of an antisense oligonucleotide-mediated exon skipping therapeutic strategy for Mucolipidosis II: validation at RNA levelpt_PT
dc.title.alternativeAntisense oligonucleotide therapy for ML IIpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleHuman Gene Therapypt_PT
rcaap.embargofctPolítica editorial da revistapt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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