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Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example

2022-04-19Journal article Open access
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dc.contributor.authorSantos, Juliana Inês
dc.contributor.authorGonçalves, Mariana
dc.contributor.authorMatos, Liliana
dc.contributor.authorMoreira, Luciana
dc.contributor.authorCarvalho, Sofia
dc.contributor.authorPrata, Maria João
dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorAlves, Sandra
dc.date.accessioned2023-01-26T15:12:30Z
dc.date.available2023-01-26T15:12:30Z
dc.date.issued2022-04-19
dc.descriptionThis article belongs to the Special Issue New Insights into Lysosomal Storage Disorders and Other Rare Genetic Diseases.pt_PT
dc.description.abstractOver recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole.pt_PT
dc.description.sponsorshipThis research was partially funded by the FCT (FCT/PTDC/BBB-BMD/6301/2014 and EXPL/BTM-SAL/0659/2021), the Portuguese Society for Metabolic Disorders (Sociedade Portuguesa de Doenças Metabólicas, SPDM—Bolsa SPDM de apoio à investigação Dr Aguinaldo Cabral 2018 (2019DGH1629/SPDM2018I&D) and 2019 (2020DGH1834)), the Sanfilippo Children’s Foundation (SCF Incubator Grant 2019: 2019DGH1656/SCF2019I&D) and the MPS Society (2019DGH1642).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationLife (Basel). 2022 Apr 19;12(5):608. doi: 10.3390/life12050608. Reviewpt_PT
dc.identifier.doi10.3390/life12050608pt_PT
dc.identifier.issn2075-1729
dc.identifier.urihttp://hdl.handle.net/10400.18/8460
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationNeurological disease modeling for Sanfilippo: a key step towards understanding and treating a rare genetic disorder
dc.relation.publisherversionhttps://www.mdpi.com/2075-1729/12/5/608pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectLysosomal Storage Diseasespt_PT
dc.subjectMucopolysaccharidosespt_PT
dc.subjectRNApt_PT
dc.subjectSplicingpt_PT
dc.subjectAntisense Oligonucleotidespt_PT
dc.subjectU1 snRNA (small nuclear RNA)pt_PT
dc.subjectSplice-switching Oligonucleotidespt_PT
dc.subjectRNA-based Therapiespt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectGenética Humanapt_PT
dc.titleSplicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Examplept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNeurological disease modeling for Sanfilippo: a key step towards understanding and treating a rare genetic disorder
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BMD%2F6301%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL%2FBTM-SAL%2F0659%2F2021/PT
oaire.citation.issue5pt_PT
oaire.citation.startPage608pt_PT
oaire.citation.titleLifept_PT
oaire.citation.volume12pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
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.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication82ca1b56-9fd8-4a11-b89d-6bc8dd3c27f1
relation.isProjectOfPublication41df0cc8-c7fb-435b-83d5-9e2249fcc86d
relation.isProjectOfPublication.latestForDiscovery82ca1b56-9fd8-4a11-b89d-6bc8dd3c27f1

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