{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:02:57Z","timestamp":1760151777579,"version":"build-2065373602"},"reference-count":117,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["FCT\/PTDC\/BBBBMD\/6301\/2014","EXPL\/BTM-SAL\/0659\/2021"],"award-info":[{"award-number":["FCT\/PTDC\/BBBBMD\/6301\/2014","EXPL\/BTM-SAL\/0659\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Portuguese Society for Metabolic Disorders (Sociedade Portuguesa de Doen\u00e7as Metab\u00f3licas, SPDM)","award":["Bolsa SPDM de apoio \u00e0 investiga\u00e7\u00e3o Dr Aguinaldo Cabral 2018 (2019DGH1629\/SPDM2018I&D)","Bolsa SPDM de apoio \u00e0 investiga\u00e7\u00e3o Dr Aguinaldo Cabral 2019 (2020DGH1834)"],"award-info":[{"award-number":["Bolsa SPDM de apoio \u00e0 investiga\u00e7\u00e3o Dr Aguinaldo Cabral 2018 (2019DGH1629\/SPDM2018I&D)","Bolsa SPDM de apoio \u00e0 investiga\u00e7\u00e3o Dr Aguinaldo Cabral 2019 (2020DGH1834)"]}]},{"DOI":"10.13039\/100013918","name":"Sanfilippo Children's Foundation","doi-asserted-by":"publisher","award":["SCF Incubator Grant 2019; 2019DGH1656\/SCF2019I&D"],"award-info":[{"award-number":["SCF Incubator Grant 2019; 2019DGH1656\/SCF2019I&D"]}],"id":[{"id":"10.13039\/100013918","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013927","name":"National MPS Society","doi-asserted-by":"publisher","award":["2019DGH1642"],"award-info":[{"award-number":["2019DGH1642"]}],"id":[{"id":"10.13039\/100013927","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Over 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.<\/jats:p>","DOI":"10.3390\/life12050608","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T22:07:26Z","timestamp":1650406046000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example"],"prefix":"10.3390","volume":"12","author":[{"given":"Juliana In\u00eas","family":"Santos","sequence":"first","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3111-4612","authenticated-orcid":false,"given":"Mariana","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Tr\u00e1s-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal"}]},{"given":"Liliana","family":"Matos","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"}]},{"given":"Luciana","family":"Moreira","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"}]},{"given":"Sofia","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Faculty of Farmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0583-1028","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Prata","sequence":"additional","affiliation":[{"name":"Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"},{"name":"i3S-Institute of Research and Innovation in Health\/IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-3622","authenticated-orcid":false,"given":"Maria Francisca","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8881-9197","authenticated-orcid":false,"given":"Sandra","family":"Alves","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge (INSA I.P.), Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41594-018-0054-4","article-title":"Tapping the RNA world for therapeutics","volume":"25","author":"Lieberman","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dhuri, K., Bechtold, C., Quijano, E., Pham, H., Gupta, A., Vikram, A., and Bahal, R. (2020). Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J. Clin. Med., 9.","DOI":"10.3390\/jcm9062004"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gagliardi, M., and Ashizawa, A.T. (2021). The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040433"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","article-title":"Splicing mutations in human genetic disorders: Examples, detection, and confirmation","volume":"59","author":"Anna","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Pereira, C., San Mill\u00e1n-Tejado, B., Gallardo-G\u00f3mez, M., P\u00e9rez-M\u00e1rquez, T., Alves-Villar, M., Melc\u00f3n-Crespo, C., Fern\u00e1ndez-Mart\u00edn, J., and Ortolano, S. (2021). Therapeutic Approaches in Lysosomal Storage Diseases. Biomolecules, 11.","DOI":"10.3390\/biom11121775"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"van Gool, R., Tucker-Bartley, A., Yang, E., Todd, N., Guenther, F., Goodlett, B., Al-Hertani, W., Bodamer, O.A., and Upadhyay, J. (2021). Targeting neurological abnormalities in lysosomal storage diseases. Trends Pharmacol. Sci., in press.","DOI":"10.1016\/j.tips.2021.11.005"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Metha, A., and Winchester, B.E. (2012). Clinical Aspects and Clinical Diagnosis. Lysosomal Storage Disorders\u2014A Practial Guide, John Wiley and Sons.","DOI":"10.1002\/9781118514672.ch3"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Mehta, A.B. (2013). The Mucopolysaccharidoses. Lysosomal Storage Disorders\u2014A Practical Guide, Wiley-Blackwell.","DOI":"10.1002\/9781118514672"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dardis, A., and Buratti, E. (2018). Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders. Genes, 9.","DOI":"10.3390\/genes9020073"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100874","DOI":"10.1016\/j.spen.2021.100874","article-title":"Update in the Mucopolysaccharidoses","volume":"37","author":"McBride","year":"2021","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1073\/pnas.74.8.3171","article-title":"Spliced segments at the 5\u2019 terminus of adenovirus 2 late mRNA","volume":"74","author":"Berget","year":"1977","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0092-8674(77)90180-5","article-title":"An amazing sequence arrangement at the 5\u2019 ends of adenovirus 2 messenger RNA","volume":"12","author":"Chow","year":"1977","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrm2777","article-title":"Mechanisms of alternative splicing regulation: Insights from molecular and genomics approaches","volume":"10","author":"Chen","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/wrna.1140","article-title":"Exon and intron definition in pre-mRNA splicing","volume":"4","author":"Baralle","year":"2013","journal-title":"Wiley Interdiscip Rev. RNA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nrm3742","article-title":"A day in the life of the spliceosome","volume":"15","author":"Matera","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"a003707","DOI":"10.1101\/cshperspect.a003707","article-title":"Spliceosome structure and function","volume":"3","author":"Will","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/nrm.2017.86","article-title":"Mechanistic insights into precursor messenger RNA splicing by the spliceosome","volume":"18","author":"Shi","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a032409","DOI":"10.1101\/cshperspect.a032409","article-title":"Molecular Mechanisms of pre-mRNA Splicing through Structural Biology of the Spliceosome","volume":"11","author":"Yan","year":"2019","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbadis.2008.09.017","article-title":"Alternative splicing and disease","volume":"1792","author":"Tazi","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"731","DOI":"10.3389\/fgene.2020.00731","article-title":"Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease","volume":"11","author":"Limeres","year":"2020","journal-title":"Front. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s00424-018-2136-x","article-title":"Alternative splicing isoforms in health and disease","volume":"470","author":"Kim","year":"2018","journal-title":"Pflugers Arch."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1261\/rna.876308","article-title":"Splicing regulation: From a parts list of regulatory elements to an integrated splicing code","volume":"14","author":"Wang","year":"2008","journal-title":"RNA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3892\/br.2014.407","article-title":"Mechanism of alternative splicing and its regulation","volume":"3","author":"Wang","year":"2015","journal-title":"Biomed. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1002\/1873-3468.13119","article-title":"Regulation of alternative mRNA splicing: Old players and new perspectives","volume":"592","author":"Dvinge","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_25","first-page":"245","article-title":"Splicing modulation therapy in the treatment of genetic diseases","volume":"7","author":"Khoo","year":"2014","journal-title":"Appl. Clin. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1073\/pnas.75.1.285","article-title":"Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide","volume":"75","author":"Stephenson","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41573-020-0075-7","article-title":"Advances in oligonucleotide drug delivery","volume":"19","author":"Roberts","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1007\/s40265-016-0657-1","article-title":"Eteplirsen: First Global Approval","volume":"76","author":"Syed","year":"2016","journal-title":"Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.cell.2016.10.050","article-title":"Exon Skipping Therapy","volume":"167","author":"Young","year":"2016","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s40265-020-01267-2","article-title":"Golodirsen: First Approval","volume":"80","author":"Heo","year":"2020","journal-title":"Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1007\/s40265-020-01339-3","article-title":"Viltolarsen: First Approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s40265-021-01512-2","article-title":"Casimersen: First Approval","volume":"81","author":"Shirley","year":"2021","journal-title":"Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1016\/S0140-6736(16)31408-8","article-title":"Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study","volume":"388","author":"Finkel","year":"2016","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/0888-7543(88)90113-9","article-title":"An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus","volume":"2","author":"Monaco","year":"1988","journal-title":"Genomics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.addr.2015.05.008","article-title":"Exon skipping therapy for Duchenne muscular dystrophy","volume":"87","author":"Kole","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/ana.23982","article-title":"Eteplirsen for the treatment of Duchenne muscular dystrophy","volume":"74","author":"Mendell","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/nat.2016.0657","article-title":"FDA Approves Eteplirsen for Duchenne Muscular Dystrophy: The Next Chapter in the Eteplirsen Saga","volume":"27","author":"Krieg","year":"2017","journal-title":"Nucleic Acid Ther."},{"key":"ref_39","unstructured":"FDA (2022, March 15). Grants Accelerated Approval to First Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation."},{"key":"ref_40","unstructured":"FDA (2022, March 15). Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/s41434-020-0156-6","article-title":"Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy","volume":"27","author":"Dzierlega","year":"2020","journal-title":"Gene Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"988","DOI":"10.2174\/138161210790883480","article-title":"Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy","volume":"16","author":"Wilton","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1101\/gad.1941310","article-title":"Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model","volume":"24","author":"Hua","year":"2010","journal-title":"Genes Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nrneurol.2015.77","article-title":"Spinal muscular atrophy--recent therapeutic advances for an old challenge","volume":"11","author":"Faravelli","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/aian.AIAN_298_17","article-title":"Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases","volume":"21","author":"Verma","year":"2018","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/nsb887","article-title":"Correction of disease-associated exon skipping by synthetic exon-specific activators","volume":"10","author":"Cartegni","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature10485","article-title":"Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model","volume":"478","author":"Hua","year":"2011","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1089\/nat.2017.0665","article-title":"FDA Approval of Nusinersen for Spinal Muscular Atrophy Makes 2016 the Year of Splice Modulating Oligonucleotides","volume":"27","year":"2017","journal-title":"Nucleic Acid Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100346","DOI":"10.1016\/j.xcrm.2021.100346","article-title":"Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine","volume":"2","author":"Chaytow","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Balestra, D., Scalet, D., Ferrarese, M., Lombardi, S., Ziliotto, N., Croes, C.C., Petersen, N., Bosma, P., Riccardi, F., and Pagani, F. (2020). A Compensatory U1snRNA Partially Rescues FAH Splicing and Protein Expression in a Splicing-Defective Mouse Model of Tyrosinemia Type I. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062136"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.omtn.2019.08.014","article-title":"Combining Engineered U1 snRNA and Antisense Oligonucleotides to Improve the Treatment of a BBS1 Splice Site Mutation","volume":"18","author":"Breuel","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.15252\/embr.201541116","article-title":"The pathogenicity of splicing defects: Mechanistic insights into pre-mRNA processing inform novel therapeutic approaches","volume":"16","author":"Daguenet","year":"2015","journal-title":"EMBO Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"628137","DOI":"10.3389\/fbioe.2021.628137","article-title":"The Limitless Future of RNA Therapeutics","volume":"9","author":"Damase","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-0716-2010-6_2","article-title":"Antisense RNA Therapeutics: A Brief Overview","volume":"2434","author":"Garanto","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/978-1-0716-2010-6_18","article-title":"Considerations for Generating Humanized Mouse Models to Test Efficacy of Antisense Oligonucleotides","volume":"2434","author":"Garanto","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1101\/gr.3108805","article-title":"Comparison of splice sites in mammals and chicken","volume":"15","author":"Abril","year":"2005","journal-title":"Genome Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"545","DOI":"10.15252\/emmm.201607199","article-title":"Delivery is key: Lessons learnt from developing splice-switching antisense therapies","volume":"9","author":"Godfrey","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.neuron.2017.04.010","article-title":"Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases","volume":"94","author":"Schoch","year":"2017","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Heon-Roberts, R., Nguyen, A.L.A., and Pshezhetsky, A.V. (2020). Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020344"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1080\/15476286.2021.2021650","article-title":"RNA-based therapeutics for neurological diseases","volume":"19","author":"Anthony","year":"2022","journal-title":"RNA Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e13243","DOI":"10.15252\/emmm.202013243","article-title":"Delivery of oligonucleotide-based therapeutics: Challenges and opportunities","volume":"13","author":"Hammond","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_62","unstructured":"Mehta, A., Beck, M., and Sunder-Plassmann, G. (2006). Epidemiology of lysosomal storage disorders: An overview. Fabry Disease: Perspectives from 5 Years of FOS, Oxford PharmaGenesis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1750-1172-9-59","article-title":"Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders","volume":"9","author":"Morey","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41572-018-0025-4","article-title":"Lysosomal storage diseases","volume":"4","author":"Platt","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13052-018-0564-z","article-title":"New treatments for the mucopolysaccharidoses: From pathophysiology to therapy","volume":"44","author":"Fecarotta","year":"2018","journal-title":"Ital. J. Pediatr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s10545-010-9075-9","article-title":"Pathophysiology of neuropathic lysosomal storage disorders","volume":"33","author":"Bellettato","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_67","first-page":"119","article-title":"Diagnostic methods for Lysosomal Storage Disease","volume":"7","author":"Mokhtariye","year":"2019","journal-title":"Rep. Biochem. Mol. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.jmoldx.2020.01.010","article-title":"Setup and Validation of a Targeted Next-Generation Sequencing Approach for the Diagnosis of Lysosomal Storage Disorders","volume":"22","author":"Zanetti","year":"2020","journal-title":"J. Mol. Diagn."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Viana, G.M., Priestman, D.A., Platt, F.M., Khan, S., Tomatsu, S., and Pshezhetsky, A.V. (2020). Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020396"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"471325","DOI":"10.1155\/2012\/471325","article-title":"Glycosaminoglycan storage disorders: A review","volume":"2012","author":"Coutinho","year":"2012","journal-title":"Biochem. Res. Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ymgme.2017.08.008","article-title":"Pathophysiology, evaluation, and management of sleep disorders in the mucopolysaccharidoses","volume":"122S","author":"Rapoport","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ymgme.2016.09.005","article-title":"Glycosaminoglycans detection methods: Applications of mass spectrometry","volume":"120","author":"Kubaski","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/imj.15100","article-title":"Treatable lysosomal storage diseases in the advent of disease-specific therapy","volume":"50","author":"Peters","year":"2020","journal-title":"Intern. Med. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13052-018-0553-2","article-title":"Biochemical and molecular analysis in mucopolysaccharidoses: What a paediatrician must know","volume":"44","author":"Filocamo","year":"2018","journal-title":"Ital. J. Pediatr."},{"key":"ref_75","unstructured":"(2022, March 14). HGMD. Available online: https:\/\/my.qiagendigitalinsights.com\/."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1136\/archdischild-2020-319040","article-title":"Improvement in time to treatment, but not time to diagnosis, in patients with mucopolysaccharidosis type I","volume":"106","author":"Giugliani","year":"2020","journal-title":"Arch. Dis. Child"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13023-017-0662-9","article-title":"Open issues in Mucopolysaccharidosis type I-Hurler","volume":"12","author":"Parini","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Kubaski, F., de Oliveira Poswar, F., Michelin-Tirelli, K., Matte, U.D.S., Horovitz, D.D., Barth, A.L., Baldo, G., Vairo, F., and Giugliani, R. (2020). Mucopolysaccharidosis Type I. Diagnostics, 10.","DOI":"10.3390\/diagnostics10030161"},{"key":"ref_79","unstructured":"Hashmi, M.S.G.V. (2022, March 15). Mucopolysaccharidosis Type II, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK560829\/."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.18103\/mra.v8i2.2045","article-title":"A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise","volume":"8","author":"Pearse","year":"2020","journal-title":"Med. Res. Arch."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s10545-008-0838-5","article-title":"Sanfilippo syndrome: A mini-review","volume":"31","author":"Valstar","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ymgme.2016.05.006","article-title":"A phase 1\/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA","volume":"118","author":"Jones","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ymgme.2018.10.006","article-title":"Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial","volume":"126","author":"Wijburg","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ymgme.2018.12.003","article-title":"Final results of the phase 1\/2, open-label clinical study of intravenous recombinant human N-acetyl-\u03b1-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB","volume":"126","author":"Whitley","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/jimd.12316","article-title":"Novel therapies for mucopolysaccharidosis type III","volume":"44","author":"Davison","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"v4","DOI":"10.1093\/rheumatology\/ker394","article-title":"Overview of the mucopolysaccharidoses","volume":"50","author":"Muenzer","year":"2011","journal-title":"Rheumatology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Sawamoto, K., Alvarez Gonzalez, J.V., Piechnik, M., Otero, F.J., Couce, M.L., Suzuki, Y., and Tomatsu, S. (2020). Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041517"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2741\/4490","article-title":"Mucopolysaccharidosis VI: Pathophysiology, diagnosis and treatment","volume":"22","author":"Harmatz","year":"2017","journal-title":"Front. Biosci. (Landmark Ed.)"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e226","DOI":"10.1016\/j.bbmt.2019.02.012","article-title":"Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future","volume":"25","author":"Taylor","year":"2019","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1136\/jmedgenet-2015-103322","article-title":"Clinical course of sly syndrome (mucopolysaccharidosis type VII)","volume":"53","author":"Montano","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5582\/irdr.2020.01011","article-title":"A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management","volume":"9","author":"Zhou","year":"2020","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s40262-018-0721-y","article-title":"Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials","volume":"58","author":"Qi","year":"2019","journal-title":"Clin. Pharm."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s40265-019-01147-4","article-title":"Therapeutic Options for Mucopolysaccharidoses: Current and Emerging Treatments","volume":"79","author":"Sawamoto","year":"2019","journal-title":"Drugs"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6296","DOI":"10.1073\/pnas.96.11.6296","article-title":"Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX","volume":"96","author":"Salo","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1007\/s10545-011-9343-3","article-title":"A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis","volume":"34","author":"Imundo","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Sato, Y., and Okuyama, T. (2020). Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020400"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"201","DOI":"10.5114\/pedm.2021.109270","article-title":"Mucopolysaccharidosis III: Molecular basis and treatment","volume":"27","author":"Spahiu","year":"2021","journal-title":"Pediatr. Endocrinol. Diabetes Metab."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1016\/j.bbadis.2015.09.011","article-title":"Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II","volume":"1852","author":"Matos","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.dib.2015.10.011","article-title":"Data in support of a functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II","volume":"5","author":"Matos","year":"2015","journal-title":"Data Brief"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ymgme.2013.08.011","article-title":"Mucopolysaccharidosis type II: Identification of 30 novel mutations among Latin American patients","volume":"111","author":"Schwartz","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Soukarieh, O., Gaildrat, P., Hamieh, M., Drouet, A., Baert-Desurmont, S., Frebourg, T., Tosi, M., and Martins, A. (2016). Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005756"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13023-014-0180-y","article-title":"Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations","volume":"9","author":"Matos","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1042\/BST0360548","article-title":"Can donor splice site recognition occur without the involvement of U1 snRNP?","volume":"36","author":"Raponi","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1042\/bse0540079","article-title":"Role of small nuclear RNAs in eukaryotic gene expression","volume":"54","author":"Valadkhan","year":"2013","journal-title":"Essays Biochem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1089\/hum.2012.110","article-title":"A gene therapeutic approach to correct splice defects with modified U1 and U6 snRNPs","volume":"24","author":"Schmid","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/mt.2011.7","article-title":"Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells","volume":"19","author":"Glaus","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ajhg.2010.08.016","article-title":"Correct mRNA processing at a mutant TT splice donor in FANCC ameliorates the clinical phenotype in patients and is enhanced by delivery of suppressor U1 snRNAs","volume":"87","author":"Hartmann","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/humu.21509","article-title":"U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation","volume":"32","author":"Schmid","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1126\/science.8266100","article-title":"Involvement of U6 snRNA in 5\u2032 splice site selection","volume":"262","author":"Seraphin","year":"1993","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1126\/science.8266093","article-title":"Mutations in U6 snRNA that alter splice site specificity: Implications for the active site","volume":"262","author":"Lesser","year":"1993","journal-title":"Science"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1023\/B:BOLI.0000042959.44318.7c","article-title":"Correlation between enzyme activity and substrate storage in a cell culture model system for Gaucher disease","volume":"27","author":"Schueler","year":"2004","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/emmm.200900036","article-title":"Treating lysosomal storage diseases with pharmacological chaperones: From concept to clinics","volume":"1","author":"Parenti","year":"2009","journal-title":"EMBO Mol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"773384","DOI":"10.3389\/fmolb.2021.773384","article-title":"Reproduction in Animal Models of Lysosomal Storage Diseases: A Scoping Review","volume":"8","author":"Vuolo","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Rigon, L., De Filippis, C., Napoli, B., Tomanin, R., and Orso, G. (2021). Exploiting the potential of drosophila models in lysosomal storage disorders: Pathological mechanisms and drug discovery. Biomedicines, 9.","DOI":"10.3390\/biomedicines9030268"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Benet\u00f3, N., Vilageliu, L., Grinberg, D., and Canals, I. (2020). Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217819"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev-genom-083118-015345","article-title":"New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases","volume":"21","author":"Hartley","year":"2020","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e1451","DOI":"10.1002\/mgg3.1451","article-title":"NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patient","volume":"8","author":"Encarnacao","year":"2020","journal-title":"Mol. Genet. Genom. Med."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/5\/608\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:56:35Z","timestamp":1760136995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/5\/608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,19]]},"references-count":117,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["life12050608"],"URL":"https:\/\/doi.org\/10.3390\/life12050608","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2022,4,19]]}}}