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Assessing the potential of RNA-based therapeutics for a group of Lysosomal Storage Diseases with neurological involvement

2021-11Conference object Open access
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dc.contributor.authorSantos, Juliana Inês
dc.contributor.authorGonçalves, Mariana
dc.contributor.authorMatos, Liliana
dc.contributor.authorGaspar, Paulo
dc.contributor.authorPires, Maria João
dc.contributor.authorOliveira, Paula
dc.contributor.authorPrata, Maria João
dc.date.accessioned2022-03-14T17:06:41Z
dc.date.available2022-03-14T17:06:41Z
dc.date.issued2021-11
dc.description.abstractDuring the first two decades of the 21st century, remarkable progresses have been achieved in the field of RNA-based therapeutics. From antisense RNA to RNA modification, the therapeutic potential of RNA-based technologies has nothing but increased. In our lab, we have been addressing the potential of different RNA-based drugs to either correct or ameliorate the sub-cellular phenotype of a number of severe, life-threatening diseases: the so-called Lysosomal Storage Disorders (LSDs). Among them, we are focusing our efforts on those which present with a predominant neurological phenotype, since there are virtually no approved treatments for any of them. Briefly, two major research lines are being pursued: the first relies on the design of mutation-specific approaches to correct abnormal splicing processes in LSD-related genes, whenever they underlie pathology. The second depends upon selective downregulation of genes involved in the biosynthethic cascades that give origin to the substrates that accumulate in each pathology. Here we present an overview on our results with both approaches on Sanfilippo syndrome, a sub-group of severe neurodegenerative LSDs. For the mutation-specific, splicing correction approach, we are using U1snRNA vectors to restore the splicing defect caused by the HGSNAT mutation c.234+1G>A, that leads to Sanfilippo C disease. We started by demonstrating in vitro that a modified U1snRNA vector designed to improve the definition of HGSNAT exon 2 could partially restore its normal splicing process. Now, we are evaluating its therapeutic potential in vivo, in mice expressing the human splicing defect. For the substrate reduction approach, we are using siRNAs. By acting over a specific biosynthethic cascade, siRNAs promote an overall decrease of the accumulating substrate. So far, we have already tested this approach in patients’ fibroblasts and observed a high inhibition of the target mRNAs and a decrease in storage. Overall, there are substantial differences between these two approaches but they also face common challenges and show equally promising results.pt_PT
dc.description.sponsorshipFCT (SFRH/BPD/101965/2014; SFRH/BD/124372/2016)pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7990
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.subjectMucopolysaccharidosis IIIpt_PT
dc.subjectLysosomal Storage Diseasespt_PT
dc.subjectDoenças Lisossomais de sobrecargapt_PT
dc.subjectMucopolissacaridose IIIpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenética Humanapt_PT
dc.titleAssessing the potential of RNA-based therapeutics for a group of Lysosomal Storage Diseases with neurological involvementpt_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.title25th Annual Meeting of the Portuguese Society of Human Genetics, 18-19 Novembro 2021pt_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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