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mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis

2025-01-31Artigo científico Acesso aberto
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dc.contributor.authorSantos, Juliana I.
dc.contributor.authorGonçalves, Mariana
dc.contributor.authorAlmeida, Matilde B.
dc.contributor.authorRocha, Hugo
dc.contributor.authorDuarte, Ana J.
dc.contributor.authorMatos, Liliana
dc.contributor.authorMoreira, Luciana V.
dc.contributor.authorEncarnação, Marisa
dc.contributor.authorGaspar, Paulo
dc.contributor.authorPrata, Maria J.
dc.contributor.authorCoutinho, Maria F.
dc.contributor.authorAlves, Sandra
dc.date.accessioned2026-01-13T13:00:05Z
dc.date.available2026-01-13T13:00:05Z
dc.date.issued2025-01-31
dc.descriptionThis article belongs to the Special Issue Peroxisome and Lysosome in Health and Disease
dc.description.abstractMucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.eng
dc.description.sponsorshipThis work was financed by national funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., within the scope of the project ASOS2cureMPSIII-2022.04667.PTDC (https://doi.org/10.54499/2022.04667.PTDC). The authors would like to thank Sanfilippo Children’s Foundation (2019DGH1656), SPDM (2019DGH1629), CECA (UIDB/00211/2020) and AL4AnimalS (LA/P/0059/2020).
dc.identifier.citationInt J Mol Sci. 2025 Feb 1;26(3):1273. doi: 10.3390/ijms26031273. Epub 2025 Jan 31
dc.identifier.doi10.3390/ijms26031273
dc.identifier.eissn1422-0067
dc.identifier.issn1661-6596
dc.identifier.pmid39941041
dc.identifier.urihttp://hdl.handle.net/10400.18/10686
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI
dc.relationDevelopment of a Genetic Substrate Reduction Therapy for MPS III using Antisense Oligonucleotides as therapeutic agents
dc.relationCenter for the Study of Animal Science
dc.relationAssociate Laboratory for Animal and Veterinary Sciences
dc.relation.hasversionhttps://www.mdpi.com/1422-0067/26/3/1273
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectLysosomal Storage Disorders (LSDs)
dc.subjectRNA Therapeutics
dc.subjectMucopolysaccharidosis type III (MPS III)
dc.subjectAntisense Oligonucleotides (ASOs)
dc.subjectGapmer ASOs
dc.subjectGenetic Substrate Reduction Therapy (gSRT)
dc.subjectDoenças Lisossomais de Sobrecarga (DLSs)
dc.subjectMucopolissacaridose tipo III
dc.subjectTerapia de RNA
dc.subjectOligonucleótidos antisense
dc.subjectGenética Humana
dc.subjectDoenças Genéticas
dc.titlemRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesiseng
dc.typejournal article
dcterms.referenceshttps://www.mdpi.com/article/10.3390/ijms26031273/s1
dspace.entity.typePublication
oaire.awardNumber2022.04667.PTDC
oaire.awardNumberUIDB/00211/2020
oaire.awardNumberLA/P/0059/2020
oaire.awardTitleDevelopment of a Genetic Substrate Reduction Therapy for MPS III using Antisense Oligonucleotides as therapeutic agents
oaire.awardTitleCenter for the Study of Animal Science
oaire.awardTitleAssociate Laboratory for Animal and Veterinary Sciences
oaire.awardURIhttp://hdl.handle.net/10400.18/10685
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00211%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0059%2F2020/PT
oaire.citation.issue3
oaire.citation.startPage1273
oaire.citation.titleInternational Journal of Molecular Sciences
oaire.citation.volume26
oaire.fundingStreamConcurso de Projetos de I&D em Todos os Domínios Científicos - 2022 - PEX
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
relation.isProjectOfPublication4fff90c8-028d-4a6e-9957-39b52f471b44
relation.isProjectOfPublication69b75eb9-6f25-4ad8-98db-6cc7e9bcdcc7
relation.isProjectOfPublication93de5af7-dedc-4696-ae11-592584b020a8
relation.isProjectOfPublication.latestForDiscovery4fff90c8-028d-4a6e-9957-39b52f471b44

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