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Genetic Substrate Reduction Therapy for Mucopolysaccharidoses type III: toward a siRNA-containing nanoparticle targeted to brain cells

2020-04Conference object Open access
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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.accessioned2021-03-13T16:18:30Z
dc.date.available2021-03-13T16:18:30Z
dc.date.issued2020-04
dc.description.abstractThe classical therapeutic approach for LSD, enzyme replacement therapy, would hardly rise as a potentially successful tool to reduce the disease burden in MPS III patients, as it is long known to have no impact on neuropathology. A tempting alternative, however, would be to block substrate accumulation upstream, by decreasing its synthesis. That concept is known as substrate reduction therapy (SRT). Having this in mind, we designed an RNA-based strategy based upon the selective downregulation of one gene involved in the very early stages of the glycosaminoglycans’ (GAG) biosynthethic cascade. Our goal is to promote an effective reduction of the accumulating substrate, ultimately decreasing or delaying MPS’ symptoms. As tools to achieve substrate reduction, we are evaluating a specific type of antisense oligonucleotides, able to trigger a naturally-occurring post-transcriptional gene silencing process called RNA interference: the small interfering RNAs (siRNAs). So far, the obtained results are quite promising with marked decreases of the target mRNA levels in all tested cell lines (MPS IIIA, IIIC and IIID patients’ fibroblasts). Currently, we are evaluating the effect of that decrease on the overall storage of GAGs 7 days post-transfection, also with promising results. Here we present an overview on the current results of this project, while discussing its next steps, namely the development and evaluation of vectors for in vivo delivery. Our goal is to develop targeted stable nucleic acid lipid particles (t-SNALPs) coupled with different ligands, which promote cell uptake of the ‘anti-GAG’ siRNAs in a variety of cells, including neurons.pt_PT
dc.description.sponsorshipbcp/LIM/DGH/Dz2015 ; FTC MFC:SFRH/BPD/101965/2014; JIS:SFRH/BD/124372/2016; Dr. Aguinaldo Cabral SPDM2018I&D/2019DGH1629pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7458
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationLess is more – substrate reduction therapy for mucopolysaccharidoses through RNAi
dc.relationRNA-based therapies for Mucopolysaccharidoses
dc.subjectLysosomal Storage Diseasespt_PT
dc.subjectRNA Therapiespt_PT
dc.subjectSubstrate Reduction Therapypt_PT
dc.subjectMPS IIIpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleGenetic Substrate Reduction Therapy for Mucopolysaccharidoses type III: toward a siRNA-containing nanoparticle targeted to brain cellspt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.awardTitleLess is more – substrate reduction therapy for mucopolysaccharidoses through RNAi
oaire.awardTitleRNA-based therapies for Mucopolysaccharidoses
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F101965%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F124372%2F2016/PT
oaire.citation.conferencePlace(online)pt_PT
oaire.citation.title1st Annual Genetics Virtual Week, 21-23 April 2020pt_PT
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
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
relation.isProjectOfPublicationd1c04e35-3f6b-4a72-bc55-d760905299ad
relation.isProjectOfPublication562a3a9f-a750-448a-a10a-3237c343b669
relation.isProjectOfPublication.latestForDiscoveryd1c04e35-3f6b-4a72-bc55-d760905299ad

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