{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:05:46Z","timestamp":1789981546138,"version":"4.0.1"},"reference-count":153,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a rare, early-onset, autosomal-dominant neurodegenerative tauopathy caused by mutations in the Microtubule-Associated Protein Tau (MAPT) gene. A subset of these mutations selectively disrupts the normal alternative splicing of MAPT exon 10, altering the physiological ratio of 3-Repeat (3R) and 4-Repeat (4R) tau isoforms; this imbalance, driving pathological tau aggregation and progressive neurodegeneration, is a pathogenic hallmark of FTDP-17. This review explores the molecular mechanisms regulating exon 10 splicing, focusing on how exonic and intronic splicing mutations destabilise mRNA structures or alter splicing factor binding, and discusses how these changes can cause disease symptoms in experimental models. It describes different research methods for studying splicing issues, including minigene reporters, cell lines, human induced pluripotent stem cell (iPSC)-derived neurons, brain organoids and mouse models that naturally express only 4R tau. It also covers potential therapeutic approaches applicable to restoring the normal 3R\/4R tau ratio. These include Antisense Oligonucleotides (ASOs), RNA interference (siRNA), Small-Molecule Splicing modulators (SMCs), Spliceosome-Mediated RNA trans-splicing (SMaRT), CRISPR-based transcript engineering, genome editing and RNA stem-loop binders. Additionally, the review highlights recent Phase 2 trial results, including the Diranersen (BIIB080) tau-lowering ASO, the development of MAPT-targeted RNA therapies, new tau-PET and plasma p-tau biomarkers, and innovative strategies to deliver CNS treatments, including non-invasive approaches. By integrating advances in RNA biology, disease modelling and targeted therapies, the review outlines potential future strategies for treating FTDP-17 and other tau-related disorders.<\/jats:p>","DOI":"10.3390\/genes17091150","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding MAPT Exon 10 Mis-Splicing in FTDP-17: From Pathogenic Mechanisms and Experimental Models to Molecular Therapies"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5660-8283","authenticated-orcid":false,"given":"Giuseppina","family":"Covello","sequence":"first","affiliation":[{"name":"Department of Biology, University of Padua, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/0896-6273(89)90210-9","article-title":"Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer\u2019s disease","volume":"3","author":"Goedert","year":"1989","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1126\/science.1132814","article-title":"A century of Alzheimer\u2019s disease and tau pathology","volume":"314","author":"Goedert","year":"2006","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/31508","article-title":"Association of missense and 5\u2019-splice-site mutations in tau with the inherited dementia FTDP-17","volume":"393","author":"Hutton","year":"1998","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7737","DOI":"10.1073\/pnas.95.13.7737","article-title":"Mutation in the tau gene in familial multiple system tauopathy with presenile dementia","volume":"95","author":"Spillantini","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/j.1750-3639.1999.tb00550.x","article-title":"Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick\u2019s disease","volume":"9","author":"Delacourte","year":"1999","journal-title":"Brain Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s004010000283","article-title":"Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick\u2019s disease, corticobasal degeneration and progressive supranuclear palsy","volume":"101","author":"Arai","year":"2001","journal-title":"Acta Neuropathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00401-021-02392-2","article-title":"Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD","volume":"143","author":"Bowles","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_8","first-page":"271","article-title":"Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2","volume":"387","author":"Neve","year":"1986","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/s41580-024-00753-9","article-title":"Cellular and pathological functions of tau","volume":"25","author":"Naguib","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10626","DOI":"10.1021\/bi00158a027","article-title":"Structure and novel exons of the human tau gene","volume":"31","author":"Andreadis","year":"1992","journal-title":"Biochemistry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.bbadis.2004.08.010","article-title":"Tau gene alternative splicing: Expression patterns, regulation and modulation of function in development and disease","volume":"1739","author":"Andreadis","year":"2005","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0165-0173(00)00019-9","article-title":"Tau protein isoforms, phosphorylation and role in neurodegenerative disorders","volume":"33","author":"Delacourte","year":"2000","journal-title":"Brain Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/nrn.2015.1","article-title":"Tau in physiology and pathology","volume":"17","author":"Wang","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1750-1326-3-8","article-title":"Tau exon 10 alternative splicing and tauopathies","volume":"3","author":"Liu","year":"2008","journal-title":"Mol. Neurodegener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"38182","DOI":"10.1074\/jbc.M007489200","article-title":"Structural and functional differences between 3-repeat and 4-repeat tau isoforms","volume":"275","author":"Goode","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/0896-6273(89)90077-9","article-title":"Developmentally regulated expression of specific tau sequences","volume":"2","author":"Kosik","year":"1989","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-021-02317-z","article-title":"A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer\u2019s disease","volume":"142","author":"Gargini","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_18","first-page":"17700","article-title":"Determinants of 4-repeat tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion","volume":"275","author":"Schellenberg","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15134","DOI":"10.1074\/jbc.274.21.15134","article-title":"5\u2019 splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10","volume":"274","author":"Grover","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/brain\/awf069","article-title":"Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene","volume":"125","author":"Richardson","year":"2002","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18997","DOI":"10.1074\/jbc.M301800200","article-title":"Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2 beta","volume":"278","author":"Jiang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1111\/j.1471-4159.2005.03552.x","article-title":"The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer\u2019s disease","volume":"96","author":"Glatz","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112211","DOI":"10.1016\/j.mad.2026.112211","article-title":"Alternative splicing in Alzheimer\u2019s disease: Driver, modifier, or consequence of neurodegeneration","volume":"232","year":"2026","journal-title":"Mech. Ageing Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100563","DOI":"10.1016\/j.xgen.2024.100563","article-title":"Lineage-specific splicing regulation of MAPT gene in the primate brain","volume":"4","author":"Recinos","year":"2024","journal-title":"Cell Genom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1046\/j.1471-4159.2003.01879.x","article-title":"Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms (htau mice)","volume":"86","author":"Andorfer","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"110055","DOI":"10.1016\/j.jneumeth.2023.110055","article-title":"Human organotypic brain slice cultures: A detailed and improved protocol for preparation and long-term maintenance","volume":"404","author":"Bak","year":"2024","journal-title":"J. Neurosci. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e202403160","DOI":"10.26508\/lsa.202403160","article-title":"Human brain slice cultures: Translational applications and ethical considerations","volume":"8","author":"Joseph","year":"2025","journal-title":"Life Sci. Alliance"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"343.e1","DOI":"10.1016\/j.neurobiolaging.2021.05.010","article-title":"A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G\\>T at the intron 9\/exon 10 of the MAPT gene","volume":"106","author":"Olszewska","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1128\/MCB.20.11.4036-4048.2000","article-title":"Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17","volume":"20","author":"Jiang","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0014-5793(98)01696-2","article-title":"FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10","volume":"443","author":"Hasegawa","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.1073\/pnas.96.10.5598","article-title":"Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements","volume":"96","author":"Poorkaj","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s004010000333","article-title":"Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells","volume":"102","author":"Iseki","year":"2001","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.stemcr.2018.06.022","article-title":"Genetically engineered iPSC-derived FTDP-17 MAPT neurons display mutation-specific neurodegenerative and neurodevelopmental phenotypes","volume":"11","author":"Verheyen","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1126\/science.282.5395.1914","article-title":"Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17","volume":"282","author":"Hong","year":"1998","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/01.WNL.0000038909.49164.4B","article-title":"Clinical and genetic studies of families with the tau N279K mutation (FTDP-17)","volume":"59","author":"Tsuboi","year":"2002","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1001\/archneur.59.6.943","article-title":"Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: A comparison of the pallidopontonigral degeneration kindred and a French family","volume":"59","author":"Tsuboi","year":"2002","journal-title":"Arch. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/S0014-5793(96)01386-5","article-title":"RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments","volume":"399","author":"Kampers","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1046\/j.1471-4159.2003.02232.x","article-title":"Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors","volume":"88","author":"Wang","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Corsi, A., Bombieri, C., Valenti, M.T., and Romanelli, M.G. (2022). Tau isoforms: Gaining insight into MAPT alternative splicing. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315383"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ymeth.2005.07.015","article-title":"Use of minigene systems to dissect alternative splicing elements","volume":"37","author":"Cooper","year":"2005","journal-title":"Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1385-299X(99)00043-4","article-title":"The in vivo minigene approach to analyze tissue-specific splicing","volume":"4","author":"Stoss","year":"1999","journal-title":"Brain Res. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-61779-767-5_3","article-title":"Minigenes to confirm exon skipping mutations","volume":"Volume 867","author":"Desviat","year":"2012","journal-title":"Exon Skipping: Methods and Protocols"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1471-4159.2004.02477.x","article-title":"A minimal length between tau exon 10 and 11 is required for correct splicing of exon 10","volume":"90","author":"Yu","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eady6759","DOI":"10.1126\/scitranslmed.ady6759","article-title":"MAPT splicing modulators reduce 4R tau and rescue tauopathy phenotypes in human neurons and in a mouse model","volume":"18","author":"Silva","year":"2026","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11218","DOI":"10.1073\/pnas.0801661105","article-title":"A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators","volume":"105","author":"Stoilov","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Covello, G., Siva, K., Adami, V., and Denti, M.A. (2023). HCS-Splice: A high-content screening method to advance the discovery of RNA splicing-modulating therapeutics. Cells, 12.","DOI":"10.20944\/preprints202306.1818.v1"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13024-017-0149-0","article-title":"The SH-SY5Y cell line in Parkinson\u2019s disease research: A systematic review","volume":"12","author":"Xicoy","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_48","first-page":"e54393","article-title":"Differentiation of the SH-SY5Y human neuroblastoma cell line","volume":"114","author":"Shipley","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.3233\/JAD-2010-091363","article-title":"An in vitro model for neuroscience: Differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons","volume":"20","author":"Agholme","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23935","DOI":"10.1038\/s41598-021-03442-1","article-title":"Optimised techniques for high-throughput screening of differentiated SH-SY5Y cells and application for neurite outgrowth assays","volume":"11","author":"Dravid","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1073\/pnas.73.7.2424","article-title":"Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor","volume":"73","author":"Greene","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"42986","DOI":"10.1074\/jbc.M105113200","article-title":"Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17","volume":"276","author":"Kalbfuss","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/00001756-200001170-00011","article-title":"Pro-apoptotic effects of tau mutations in chromosome 17 frontotemporal dementia and parkinsonism","volume":"11","author":"Furukawa","year":"2000","journal-title":"Neuroreport"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.neuint.2013.03.008","article-title":"Differentiated NSC-34 motoneuron-like cells as experimental model for cholinergic neurodegeneration","volume":"62","author":"Maier","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.celrep.2017.01.013","article-title":"Altered tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes","volume":"18","author":"Ishigaki","year":"2017","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Donato, R., Miljan, E.A., Hines, S.J., Aouabdi, S., Pollock, K., Patel, S., Edwards, F.A., and Sinden, J.D. (2007). Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci., 8.","DOI":"10.1186\/1471-2202-8-36"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sindi, G., Ismael, S., Uddin, R., Slepchenko, K.G., Colvin, R.A., and Lee, D. (2024). Endogenous tau released from human ReNCell VM cultures by neuronal activity is phosphorylated at multiple sites. bioRxiv.","DOI":"10.1101\/2024.06.02.597022"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/hipo.20255","article-title":"Expression of embryonic tau protein isoforms persist during adult neurogenesis in the hippocampus","volume":"17","author":"Bullmann","year":"2007","journal-title":"Hippocampus"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, F., Merch\u00e1n-Rubira, J., Vall\u00e9s-Saiz, L., Rodr\u00edguez-Matell\u00e1n, A., and Avila, J. (2020). Differences between human and murine tau at the N-terminal end. Front. Aging Neurosci., 12.","DOI":"10.3389\/fnagi.2020.00011"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1093\/brain\/awv222","article-title":"Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations","volume":"138","author":"Iovino","year":"2015","journal-title":"Brain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"34904","DOI":"10.1038\/srep34904","article-title":"Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons","volume":"6","author":"Imamura","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/s41419-021-04007-w","article-title":"Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia","volume":"12","author":"Kopach","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13024-015-0042-7","article-title":"Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells","volume":"10","author":"Wren","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ritter, M.L., Avila, J., Garc\u00eda-Escudero, V., Hern\u00e1ndez, F., and P\u00e9rez, M. (2018). Frontotemporal dementia-associated N279K tau mutation localizes at the nuclear compartment. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00202"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.1093\/hmg\/ddv246","article-title":"Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10+16 splice-site mutation in MAPT","volume":"24","author":"Sposito","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.stemcr.2015.06.001","article-title":"Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein","volume":"5","author":"Ehrlich","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4547","DOI":"10.1016\/j.cell.2021.07.003","article-title":"ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids","volume":"184","author":"Bowles","year":"2021","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nature22047","article-title":"Cell diversity and network dynamics in photosensitive human brain organoids","volume":"545","author":"Quadrato","year":"2017","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"101541","DOI":"10.1016\/j.scr.2019.101541","article-title":"Detection of all adult Tau isoforms in a 3D culture model of iPSC-derived neurons","volume":"40","author":"Miguel","year":"2019","journal-title":"Stem Cell Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e70419","DOI":"10.1002\/alz.70419","article-title":"Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia","volume":"21","author":"Cordella","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Nogueira, G.O., Garcez, P.P., Bardy, C., Cunningham, M.O., and Sebollela, A. (2022). Modeling the human brain with ex vivo slices and in vitro organoids for translational neuroscience. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.838594"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1038\/s41593-021-00923-4","article-title":"Human ALS\/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology","volume":"24","author":"Wenger","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s40478-024-01784-1","article-title":"Human post-mortem organotypic brain slice cultures: A tool to study pathomechanisms and test therapies","volume":"12","author":"Plug","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"eaag0481","DOI":"10.1126\/scitranslmed.aag0481","article-title":"Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy","volume":"9","author":"DeVos","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ajpath.2013.03.015","article-title":"Neurodegenerative disorder FTDP-17-related tau intron 10 +16C\\>T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice","volume":"183","author":"Umeda","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/78078","article-title":"Neurofibrillary tangles, amyotrophy, and progressive motor disturbance in mice expressing a mutant (P301L) tau protein","volume":"25","author":"Lewis","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1126\/science.1113694","article-title":"Tau suppression in a neurodegenerative mouse model improves memory function","volume":"309","author":"Santacruz","year":"2005","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"12887","DOI":"10.1523\/JNEUROSCI.2107-13.2013","article-title":"Antisense reduction of tau in adult mice protects against seizures","volume":"33","author":"DeVos","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"9155","DOI":"10.1523\/JNEUROSCI.5492-06.2007","article-title":"The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model","volume":"27","author":"Dawson","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5704","DOI":"10.1016\/j.febslet.2005.09.047","article-title":"Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibrillary tangle formation","volume":"579","author":"Taniguchi","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wood, M., Yin, H., and McClorey, G. (2007). Modulating the expression of disease genes with RNA-based therapy. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030109"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nature24644","article-title":"Programmable base editing of A\u2022T to G\u2022C in genomic DNA without DNA cleavage","volume":"551","author":"Gaudelli","year":"2017","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41586-019-1711-4","article-title":"Search-and-replace genome editing without double-strand breaks or donor DNA","volume":"576","author":"Anzalone","year":"2019","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1089\/nat.2013.0461","article-title":"Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases","volume":"24","author":"Siva","year":"2014","journal-title":"Nucleic Acid Ther."},{"key":"ref_87","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_88","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/s41591-023-02326-3","article-title":"Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer\u2019s disease: A phase 1b, randomized, placebo-controlled trial","volume":"29","author":"Mummery","year":"2023","journal-title":"Nat. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41392-020-0207-x","article-title":"Therapeutic siRNA: State of the art","volume":"5","author":"Hu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2174\/156652321405140926160602","article-title":"Tau silencing by siRNA in the P301S mouse model of tauopathy","volume":"14","author":"Xu","year":"2014","journal-title":"Curr. Gene Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7195","DOI":"10.1073\/pnas.1231012100","article-title":"Allele-specific silencing of dominant disease genes","volume":"100","author":"Miller","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1093\/nar\/gkh208","article-title":"Targeting Alzheimer\u2019s disease genes with RNA interference: An efficient strategy for silencing mutant alleles","volume":"32","author":"Miller","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_94","unstructured":"Covello, G., Siva, K., and Denti, M.A. (2016). RNA Interference Mediated Therapy for Neurodegenerative Diseases. (Patent WO2016151523A1)."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"102437","DOI":"10.1016\/j.omtn.2024.102437","article-title":"Development, opportunities, and challenges of siRNA nucleic acid drugs","volume":"36","author":"Xiao","year":"2025","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s40265-020-01269-0","article-title":"Givosiran: First approval","volume":"80","author":"Scott","year":"2020","journal-title":"Drugs"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s40265-020-01463-0","article-title":"Lumasiran: First approval","volume":"81","author":"Scott","year":"2021","journal-title":"Drugs"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1093\/ehjcvp\/pvab014","article-title":"Inclisiran: A new milestone on the PCSK9 road to tackle cardiovascular risk","volume":"7","author":"Santulli","year":"2021","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1124\/molpharm.124.000895","article-title":"The growing class of novel RNAi therapeutics","volume":"106","author":"Traber","year":"2024","journal-title":"Mol. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.molmed.2023.10.005","article-title":"Three \u2018E\u2019 challenges for siRNA drug development","volume":"30","author":"Guo","year":"2024","journal-title":"Trends Mol. Med."},{"key":"ref_102","unstructured":"Padda, I.S., Mahtani, A.U., Patel, P., and Parmar, M. (2026). Small Interfering RNA (siRNA) Therapy. StatPearls, StatPearls Publishing."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"102503","DOI":"10.1016\/j.omtn.2025.102503","article-title":"Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes","volume":"36","author":"Sahashi","year":"2025","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1001\/jamaneurol.2023.3861","article-title":"Exploratory tau biomarker results from a multiple ascending-dose study of BIIB080 in Alzheimer disease: A randomized clinical trial","volume":"80","author":"Edwards","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-pharmtox-010716-104846","article-title":"Pharmacology of antisense drugs","volume":"57","author":"Bennett","year":"2017","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1038\/mtna.2014.30","article-title":"Antisense-mediated exon skipping decreases tau protein expression: A potential therapy for tauopathies","volume":"3","author":"Sud","year":"2014","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s43587-025-01031-9","article-title":"Exploratory analyses of clinical outcomes from the BIIB080 phase 1b study in mild Alzheimer\u2019s disease","volume":"6","author":"Shulman","year":"2026","journal-title":"Nat. Aging"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"803","DOI":"10.4103\/NRR.NRR-D-23-02057","article-title":"Antisense oligonucleotides provide optimism to the therapeutic landscape for tauopathies","volume":"20","author":"Harris","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1002\/cbic.201402069","article-title":"Bottom-up design of small molecules that stimulate exon 10 skipping in mutant MAPT pre-mRNA","volume":"15","author":"Luo","year":"2014","journal-title":"ChemBioChem"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"8706","DOI":"10.1021\/jacs.0c00768","article-title":"Design, optimization, and study of small molecules that target tau pre-mRNA and affect splicing","volume":"142","author":"Chen","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Tang, Z., Zhao, J., Pearson, Z.J., Boskovic, Z.V., and Wang, J. (2021). RNA-targeting splicing modifiers: Drug development and screening assays. Molecules, 26.","DOI":"10.3390\/molecules26082263"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1021\/acschembio.5c00260","article-title":"Design of an orally bioavailable small molecule that modulates the microtubule-associated protein tau\u2019s pre-mRNA splicing","volume":"20","author":"Zhang","year":"2025","journal-title":"ACS Chem. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6501","DOI":"10.1021\/acs.jmedchem.8b00741","article-title":"Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA)","volume":"61","author":"Ratni","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nchembio.1837","article-title":"SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice","volume":"11","author":"Palacino","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_115","first-page":"E4604","article-title":"Mechanistic studies of a small-molecule modulator of SMN2 splicing","volume":"115","author":"Wang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1038\/s41467-021-23663-2","article-title":"A deep learning approach to identify gene targets of a therapeutic for human splicing disorders","volume":"12","author":"Gao","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/nyas.14051","article-title":"Small molecule targeting of RNA structures in neurological disorders","volume":"1471","author":"Angelbello","year":"2020","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.molmed.2015.11.005","article-title":"Small molecule modulators of pre-mRNA splicing in cancer therapy","volume":"22","author":"Salton","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.ajhg.2023.01.019","article-title":"Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia","volume":"110","author":"Morini","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"15659","DOI":"10.1073\/pnas.0503150102","article-title":"Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: Implications for tauopathies","volume":"102","author":"Mansfield","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/6986","article-title":"Spliceosome-mediated RNA trans-splicing as a tool for gene therapy","volume":"17","author":"Puttaraju","year":"1999","journal-title":"Nat. Biotechnol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1093\/hmg\/ddp264","article-title":"Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing","volume":"18","author":"Anthony","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1093\/hmg\/ddt108","article-title":"Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing","volume":"22","author":"Avale","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Mu\u00f1iz, J.A., Facal, C.L., Urrutia, L., Clerici-Delville, R., Damianich, A., Ferrario, J.E., Falasco, G., and Avale, M.E. (2022). SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.951384"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature17946","article-title":"Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage","volume":"533","author":"Komor","year":"2016","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41551-024-01233-3","article-title":"Systematic optimization of prime editing for the efficient functional correction of CFTR F508del in human airway epithelial cells","volume":"9","author":"Sousa","year":"2025","journal-title":"Nat. Biomed. Eng."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"102734","DOI":"10.1016\/j.omtn.2025.102734","article-title":"Prime editing corrects the dilated cardiomyopathy causing RBM20-P633L-mutation in human cardiomyocytes","volume":"36","author":"Roman","year":"2025","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s41587-023-01758-z","article-title":"Efficient prime editing in mouse brain, liver and heart with dual AAVs","volume":"42","author":"Davis","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Shirguppe, S., Gapinske, M., Swami, D., Shenouda, K., Miskalis, A., Gosstola, N., Del Bosque Siller, D., Guerra, I., Acharya, P., and Joulani, D. (2026). In vivo CRISPR base editing for treatment of Huntington\u2019s disease. Nat. Biomed. Eng.","DOI":"10.1038\/s41551-026-01747-y"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Xu, X. (2026). Strategies of AAV capsid engineering for targeted delivery to brain, muscle, and retina. Front. Mol. Biosci., 12.","DOI":"10.3389\/fmolb.2025.1750807"},{"key":"ref_131","first-page":"22302","article-title":"Stabilization of the MAPT exon 10-intron 10 regulatory stem-loop structure by structure-specific aminoglycoside binders","volume":"281","author":"Donahue","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1093\/nar\/28.3.710","article-title":"Structural basis for recognition of the RNA major groove in the tau exon 10 splicing regulatory element by aminoglycoside antibiotics","volume":"28","author":"Varani","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Yang, L., Yin, Y., Liu, X., and Guo, B. (2026). Aptamer-Based Delivery of Genes and Drugs Across the Blood\u2013Brain Barrier. Pharmaceuticals, 19.","DOI":"10.3390\/ph19010164"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"e202402007","DOI":"10.1002\/anie.202402007","article-title":"Functional selection of tau oligomerization-inhibiting aptamers","volume":"63","author":"Wang","year":"2024","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1021\/acs.molpharmaceut.6b00165","article-title":"Inhibitory RNA aptamers of tau oligomerization and their neuroprotective roles against proteotoxic stress","volume":"13","author":"Kim","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.2174\/1381612826666200316130128","article-title":"Brain drug delivery: Overcoming the blood-brain barrier to treat tauopathies","volume":"26","author":"Hanes","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nbt.3765","article-title":"The chemical evolution of oligonucleotide therapies of clinical utility","volume":"35","author":"Khvorova","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrg.2015.3","article-title":"Pre-mRNA splicing in disease and therapeutics","volume":"17","author":"Scotti","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_139","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_140","unstructured":"ClinicalTrials.gov (2026, August 10). A First-In-Human Study of LY3954068 in Participants with Early Symptomatic Alzheimer\u2019s Disease. Identifier NCT06297590, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06297590."},{"key":"ref_141","unstructured":"ClinicalTrials.gov (2026, August 01). A Study to Evaluate the Efficacy of NIO752 in Participants with Progressive Supranuclear Palsy. Identifier NCT07498426, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07498426."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e077322","DOI":"10.1002\/alz.077322","article-title":"Design of a phase 2, randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy, safety, and tolerability of BIIB080 in subjects with mild cognitive impairment due to Alzheimer\u2019s disease or mild Alzheimer\u2019s disease dementia","volume":"19","author":"Ziogas","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_143","unstructured":"Biogen Inc. (2026, August 10). Biogen Presents Phase 2 CELIA Data at AAIC Demonstrating Meaningful Clinical Outcomes and Robust Tau Reduction with Diranersen in Early Alzheimer\u2019s Disease, Biogen Investor Relations, Available online: https:\/\/biogen.gcs-web.com\/news-releases\/news-release-details\/biogen-presents-phase-2-celia-data-aaic-demonstrating-meaningful."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.nmd.2019.09.007","article-title":"Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the phase 2 NURTURE study","volume":"29","author":"Bertini","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/CND.0000000000000333","article-title":"Delivery of nusinersen through an Ommaya reservoir in spinal muscular atrophy","volume":"22","author":"Iannaccone","year":"2021","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Schreiner, T.G., Men\u00e9ndez-Gonz\u00e1lez, M., Schreiner, O.D., and Ciobanu, R.C. (2025). Intrathecal therapies for neurodegenerative diseases: A review of current approaches and the urgent need for advanced delivery systems. Biomedicines, 13.","DOI":"10.3390\/biomedicines13092167"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"e610","DOI":"10.1097\/BPO.0000000000001247","article-title":"Preliminary safety and tolerability of a novel subcutaneous intrathecal catheter system for repeated outpatient dosing of nusinersen to children and adults with spinal muscular atrophy","volume":"38","author":"Strauss","year":"2018","journal-title":"J. Pediatr. Orthop."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Shah, P., Lalan, M., and Barve, K. (2022). Intranasal delivery: An attractive route for the administration of nucleic acid based therapeutics for CNS disorders. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.974666"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1038\/s41467-018-04529-6","article-title":"Blood\u2013brain barrier opening in Alzheimer\u2019s disease using MR-guided focused ultrasound","volume":"9","author":"Lipsman","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"9255","DOI":"10.1038\/s41598-019-45577-2","article-title":"Ultrasound-mediated blood\u2013brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody","volume":"9","author":"Janowicz","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"e45457","DOI":"10.7554\/eLife.45457","article-title":"Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models","volume":"8","author":"Silva","year":"2019","journal-title":"eLife"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"134919","DOI":"10.1016\/j.neulet.2020.134919","article-title":"Targeting tau: Clinical trials and novel therapeutic approaches","volume":"731","author":"VandeVrede","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S1474-4422(21)00214-3","article-title":"Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer\u2019s disease and frontotemporal lobar degeneration: A retrospective diagnostic performance study","volume":"20","author":"Thijssen","year":"2021","journal-title":"Lancet Neurol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1150\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:25:28Z","timestamp":1789979128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":153,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091150"],"URL":"https:\/\/doi.org\/10.3390\/genes17091150","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}