{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:04:22Z","timestamp":1793030662867,"version":"4.5.0"},"reference-count":109,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Florida State University startup fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Fragile X Syndrome (FXS) presents with a constellation of phenotypes, including trouble regulating emotion and aggressive behaviors, disordered sleep, intellectual impairments, and atypical physical development. Genetic study of the X chromosome revealed that substantial repeat expansion of the 5\u2032 end of the gene fragile X messenger ribonucleoprotein 1 (FMR1) promoted DNA methylation and, consequently, silenced expression of FMR1. Further analysis proved that shorter repeat expansions in FMR1 also manifested in disease at later stages in life. Treatment and therapy options do exist, but they only manage symptoms. Up to now, no cure for FMR1 disorders exists. In this review, we aim to provide an overview of FMR1 biology and the latest research focused on developing therapeutic interventions that can potentially prevent and\/or reverse FXS.<\/jats:p>","DOI":"10.3390\/cells13242100","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T08:56:32Z","timestamp":1734512192000},"page":"2100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["FMR1 Disorders: Basics of Biology and Therapeutics in Development"],"prefix":"10.3390","volume":"13","author":[{"given":"Drew A.","family":"Gillett","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3416-5887","authenticated-orcid":false,"given":"Helene","family":"Tigro","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4347-7063","authenticated-orcid":false,"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3871-3420","authenticated-orcid":false,"given":"Zucai","family":"Suo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"ref_1","unstructured":"Stone, W.L., Basit, H., Shah, M., and Los, E. (2024). StatPearls, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17065","DOI":"10.1038\/nrdp.2017.65","article-title":"Fragile X syndrome","volume":"3","author":"Hagerman","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1126\/science.1675488","article-title":"Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n","volume":"252","author":"Kremer","year":"1991","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1126\/science.252.5009.1179","article-title":"Fragile X genotype characterized by an unstable region of DNA","volume":"252","author":"Yu","year":"1991","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1399-0004.2011.01723.x","article-title":"CGG repeat in the FMR1 gene: Size matters","volume":"80","author":"Willemsen","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/ajmg.b.30482","article-title":"CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor\/ataxia syndrome (FXTAS)","volume":"144B","author":"Tassone","year":"2007","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1093\/humrep\/der168","article-title":"Increased frequency of occult fragile X-associated primary ovarian insufficiency in infertile women with evidence of impaired ovarian function","volume":"26","author":"Karimov","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1093\/cercor\/10.10.1038","article-title":"Dendritic spine structural anomalies in fragile-X mental retardation syndrome","volume":"10","author":"Irwin","year":"2000","journal-title":"Cereb. Cortex"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/1096-8628(20010115)98:2<161::AID-AJMG1025>3.0.CO;2-B","article-title":"Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: A quantitative examination","volume":"98","author":"Irwin","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pbiomolbio.2018.07.001","article-title":"Handling FMRP and its molecular partners: Structural insights into Fragile X Syndrome","volume":"141","author":"Cicconardi","year":"2019","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cabal-Herrera, A.M., Tassanakijpanich, N., Salcedo-Arellano, M.J., and Hagerman, R.J. (2020). Fragile X-Associated Tremor\/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124391"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/WCO.0000000000000954","article-title":"FXTAS: Pathophysiology and Management","volume":"34","author":"Hagerman","year":"2021","journal-title":"Curr. Opin. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41583-021-00432-0","article-title":"The Molecular Biology of FMRP: New Insights into Fragile X Syndrome","volume":"22","author":"Richter","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1038\/s41380-019-0629-4","article-title":"Post-translational modifications of the Fragile X Mental Retardation Protein in neuronal function and dysfunction","volume":"25","author":"Prieto","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1002\/ajmg.a.61165","article-title":"Expansions and contractions of the FMR1 CGG repeat in 5508 transmissions of normal, intermediate, and premutation alleles","volume":"179","author":"Nolin","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/gim.2012.34","article-title":"AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome","volume":"14","author":"Yrigollen","year":"2012","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1093\/hmg\/ddu586","article-title":"Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain","volume":"24","author":"Myrick","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6634","DOI":"10.1038\/ncomms7634","article-title":"The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers","volume":"6","author":"Hu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12964-021-00741-y","article-title":"Types of nuclear localization signals and mechanisms of protein import into the nucleus","volume":"19","author":"Lu","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1111\/j.1742-4658.2008.06411.x","article-title":"Structure and function of KH domains","volume":"275","author":"Valverde","year":"2008","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/ng0193-31","article-title":"A point mutation in the FMR-1 gene associated with fragile X mental retardation","volume":"3","author":"Verkerk","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1748","DOI":"10.1002\/wrna.1748","article-title":"The RGG motif proteins: Interactions, functions, and regulations","volume":"14","author":"Chowdhury","year":"2023","journal-title":"WIREs RNA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1039\/b812537f","article-title":"Fragile X mental retardation protein recognition of G quadruplex structure per se is sufficient for high affinity binding to RNA","volume":"4","author":"Bole","year":"2008","journal-title":"Mol. BioSyst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5402","DOI":"10.1093\/nar\/gkl655","article-title":"Quadruplex DNA: Sequence, topology and structure","volume":"34","author":"Burge","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/ng0193-36","article-title":"Tissue specific expression of FMR\u20131 provides evidence for a functional role in fragile X syndrome","volume":"3","author":"Hinds","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.neuron.2008.10.004","article-title":"Fragile X syndrome: Loss of local mRNA regulation alters synaptic development and function","volume":"60","author":"Bassell","year":"2008","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7116","DOI":"10.1523\/JNEUROSCI.2802-14.2015","article-title":"Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome","volume":"35","author":"Ifrim","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.biochi.2015.02.005","article-title":"Fragile X Mental Retardation Protein: A Paradigm for Translational Control by RNA-Binding Proteins","volume":"114","author":"Chen","year":"2015","journal-title":"Biochimie"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.1016\/j.molcel.2022.10.018","article-title":"Integrative omics indicate FMRP sequesters mRNA from translation and deadenylation in human neuronal cells","volume":"82","author":"Kurosaki","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cell.2011.06.013","article-title":"FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism","volume":"146","author":"Darnell","year":"2011","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1101\/gad.1276805","article-title":"Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes","volume":"19","author":"Darnell","year":"2005","journal-title":"Genes Dev."},{"key":"ref_32","first-page":"3936","article-title":"Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets","volume":"27","author":"Zhang","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Edupuganti, R.R., Geiger, S., Lindeboom, R.G.H., Shi, H., Hsu, P.J., Lu, Z., Wang, S.-Y., Baltissen, M.P.A., Jansen, P.W.T.C., and Rossa, M. (2017). N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat. Struct. Mol. Biol., 24.","DOI":"10.1038\/nsmb.3462"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.celrep.2019.06.072","article-title":"FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export","volume":"28","author":"Edens","year":"2019","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nature24041","article-title":"Dynamic landscape and regulation of RNA editing in mammals","volume":"550","author":"Tan","year":"2017","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Shamay-Ramot, A., Khermesh, K., Porath, H.T., Barak, M., Pinto, Y., Wachtel, C., Zilberberg, A., Lerer-Goldshtein, T., Efroni, S., and Levanon, E.Y. (2015). Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005702"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/nn.2950","article-title":"Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein","volume":"14","author":"Bhogal","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Reich, D.P., and Bass, B.L. (2019). Mapping the dsRNA World. Cold Spring Harb. Perspect. Biol., 11.","DOI":"10.1101\/cshperspect.a035352"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108720","DOI":"10.1016\/j.heares.2023.108720","article-title":"Axonal and presynaptic FMRP: Localization, signal, and functional implications","volume":"430","author":"Wang","year":"2023","journal-title":"Hear. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41583-021-00445-9","article-title":"Channelopathies in fragile X syndrome","volume":"22","author":"Deng","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.cell.2008.07.031","article-title":"The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP","volume":"134","author":"Napoli","year":"2008","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/tra.12733","article-title":"Regulation of RNA granules by FMRP and implications for neurological diseases","volume":"21","author":"Lai","year":"2020","journal-title":"Traffic"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14349","DOI":"10.1523\/JNEUROSCI.2969-07.2007","article-title":"FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A","volume":"27","author":"Narayanan","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.molcel.2011.05.006","article-title":"Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling","volume":"42","author":"Muddashetty","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.neuron.2006.07.005","article-title":"Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression","volume":"51","author":"Hou","year":"2006","journal-title":"Neuron"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41467-018-03222-y","article-title":"Sumoylation regulates FMRP-mediated dendritic spine elimination and maturation","volume":"9","author":"Khayachi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1093\/hmg\/ddq007","article-title":"Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA","volume":"19","author":"Blackwell","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1242\/jcs.02882","article-title":"Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP","volume":"119","author":"Dolzhanskaya","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Brackett, D.M., Qing, F., Amieux, P.S., Sellers, D.L., Horner, P.J., and Morris, D.R. (2013). Fmr1 Transcript Isoforms: Association with Polyribosomes; Regional and Developmental Expression in Mouse Brain. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058296"},{"key":"ref_50","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). FMR1 Disorders. GeneReviews\u00ae, University of Washington."},{"key":"ref_51","unstructured":"Harper-Harrison, G., Carlson, K., and Shanahan, M.M. (2024). Hormone Replacement Therapy. StatPearls, StatPearls Publishing."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Tassanakijpanich, N., Cohen, J., Cohen, R., Srivatsa, U.N., and Hagerman, R.J. (2020). Cardiovascular Problems in the Fragile X Premutation. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.586910"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.neuron.2013.03.026","article-title":"CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome","volume":"78","author":"Todd","year":"2013","journal-title":"Neuron"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1073\/pnas.1013343108","article-title":"Non-ATG\u2013initiated translation directed by microsatellite expansions","volume":"108","author":"Zu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","unstructured":"ClinicalTrials.gov (2024, December 17). Evaluating the Neurophysiologic and Clinical Effects of Single Dose Drug Challenge, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05418049?cond=NCT05418049&rank=1."},{"key":"ref_56","unstructured":"ClinicalTrials.gov (2024, December 17). Placebo-Controlled, Single-Dose Challenge Study of Gaboxadol in Adult Males With Fragile X Syndrome (FXS), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06334419?cond=NCT06334419&rank=1."},{"key":"ref_57","unstructured":"ClinicalTrials.gov (2024, December 17). Trial of Sertraline to Treat Children With Fragile X Syndrome, Available online: https:\/\/clinicaltrials.gov\/study\/NCT01474746?cond=NCT01474746&rank=1."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1097\/YCO.0000000000000674","article-title":"Emerging Therapies and challenges for individuals with Angelman syndrome","volume":"34","author":"Heussler","year":"2021","journal-title":"Curr. Opin. Psychiatry"},{"key":"ref_59","unstructured":"ClinicalTrials.gov (2024, December 17). An Investigation of Psilocybin on Behavioural and Cognitive Symptoms of Adults With Fragile X Syndrome, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05832255?cond=NCT05832255&rank=1."},{"key":"ref_60","unstructured":"ClinicalTrials.gov (2024, December 17). CTH120 First-in-Human Study: Single and Multiple Ascending Doses and Potential Food Interaction (FIH-CTH120), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06480968?cond=NCT06480968&rank=1."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/s41591-021-01321-w","article-title":"Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: A randomized, placebo-controlled, phase 2 clinical trial","volume":"27","author":"Harnett","year":"2021","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s11689-022-09466-6","article-title":"A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)","volume":"14","author":"Hagerman","year":"2022","journal-title":"J. Neurodev. Disord."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Proteau-Lemieux, M., Lacroix, A., Galarneau, L., Corbin, F., Lepage, J.-F., and \u00c7aku, A. (2021). The safety and efficacy of metformin in fragile X syndrome: An open-label study. Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 110.","DOI":"10.1016\/j.pnpbp.2021.110307"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e956","DOI":"10.1002\/mgg3.956","article-title":"Metformin treatment in young children with fragile X syndrome","volume":"7","author":"Biag","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/cge.13039","article-title":"Metformin as targeted treatment in fragile X syndrome","volume":"93","author":"Dy","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Chadman, K.K., Adayev, T., Udayan, A., Ahmed, R., Dai, C.-L., Goodman, J.H., Meeker, H., Dolzhanskaya, N., and Velinov, M. (2023). Efficient Delivery of FMR1 across the Blood Brain Barrier Using AAVphp Construct in Adult FMR1 KO Mice Suggests the Feasibility of Gene Therapy for Fragile X Syndrome. Genes, 14.","DOI":"10.3390\/genes14020505"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1038\/npp.2014.167","article-title":"Reduced Phenotypic Severity Following Adeno-Associated Virus-Mediated Fmr1 Gene Delivery in Fragile X Mice","volume":"39","author":"Gholizadeh","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/hmg\/5.1.95","article-title":"Alternative Splicing of Exon 14 Determines Nuclear or Cytoplasmic Localisation of FMR1 Protein Isoforms","volume":"5","author":"Sittler","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.3892\/mmr.2015.3574","article-title":"Alternatively spliced products lacking exon 12 dominate the expression of fragile X mental retardation 1 gene in human tissues","volume":"12","author":"Fu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1136\/jmedgenet-2014-102593","article-title":"Differential increases of specific FMR1 mRNA isoforms in premutation carriers","volume":"52","author":"Pretto","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.omtm.2021.06.013","article-title":"Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity","volume":"22","author":"Hooper","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/gt.2009.83","article-title":"Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome","volume":"16","author":"Zeier","year":"2009","journal-title":"Gene Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1089\/hum.2016.090","article-title":"FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype","volume":"27","author":"Arsenault","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.omtm.2022.10.002","article-title":"Gene therapy using human FMRP isoforms driven by the human FMR1 promoter rescues fragile X syndrome mouse deficits","volume":"27","author":"Jiang","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e2302534120","DOI":"10.1073\/pnas.2302534120","article-title":"Antisense oligonucleotide rescue of CGG expansion\u2013dependent FMR1 mis-splicing in fragile X syndrome restores FMRP","volume":"120","author":"Shah","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","unstructured":"Ratko, T.A., Marbella, A., Godfrey, S., and Aronson, N. (2013). Enzyme-Replacement Therapies for Lysosomal Storage Diseases [Internet], Agency for Healthcare Research and Quality (US)."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1016\/j.cell.2021.08.002","article-title":"Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic","volume":"184","author":"Logan","year":"2021","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"101142","DOI":"10.1016\/j.nantod.2021.101142","article-title":"Role of nanotechnology behind the success of mRNA vaccines for COVID-19","volume":"38","author":"Khurana","year":"2021","journal-title":"Nano Today"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41593-020-0590-1","article-title":"A native function for RAN translation and CGG repeats in regulating Fragile X protein synthesis","volume":"23","author":"Rodriguez","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41467-021-21021-w","article-title":"Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats","volume":"12","author":"Derbis","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1089\/hum.2012.212","article-title":"Antisense Oligonucleotides: Rising Stars in Eliminating RNA Toxicity in Myotonic Dystrophy","volume":"24","author":"Gao","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.neuron.2016.04.006","article-title":"Gain of toxicity from ALS\/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs","volume":"90","author":"Jiang","year":"2016","journal-title":"Neuron"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicle"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/tra.12715","article-title":"Life in the lumen: The multivesicular endosome","volume":"21","author":"Gruenberg","year":"2020","journal-title":"Traffic"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"jcs216499","DOI":"10.1242\/jcs.216499","article-title":"The enigmatic endosome\u2014Sorting the ins and outs of endocytic trafficking","volume":"131","author":"Naslavsky","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/j.gendis.2022.03.021","article-title":"The biogenesis and secretion of exosomes and multivesicular bodies (MVBs): Intercellular shuttles and implications in human diseases","volume":"10","author":"Xu","year":"2023","journal-title":"Genes Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nature07961","article-title":"The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins","volume":"458","author":"Raiborg","year":"2009","journal-title":"Nature"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"R116","DOI":"10.1016\/j.cub.2012.01.028","article-title":"The ESCRT machinery","volume":"22","author":"Schmidt","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1080\/21541248.2016.1264352","article-title":"New insights into the function of Rab GTPases in the context of exosomal secretion","volume":"9","author":"Blanc","year":"2017","journal-title":"Small GTPases"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/febs.15453","article-title":"Rab family of small GTPases: An updated view on their regulation and functions","volume":"288","author":"Homma","year":"2021","journal-title":"FEBS J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/s41467-019-09720-x","article-title":"KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a","volume":"10","author":"Song","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Hade, M.D., Suire, C.N., and Suo, Z. (2021). Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine. Cells, 10.","DOI":"10.3390\/cells10081959"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1002\/med.21918","article-title":"Extracellular vesicles: Emerging frontiers in wound healing","volume":"42","author":"Hade","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Seay, T.W., and Suo, Z. (2023). Roles of Extracellular Vesicles on the Progression and Metastasis of Hepatocellular Carcinoma. Cells, 12.","DOI":"10.3390\/cells12141879"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Klyachko, N.L., Arzt, C.J., Li, S.M., Gololobova, O.A., and Batrakova, E.V. (2020). Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12121171"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Du, S., Guan, Y., Xie, A., Yan, Z., Gao, S., Li, W., Rao, L., Chen, X., and Chen, T. (2023). Extracellular vesicles: A rising star for therapeutics and drug delivery. J. Nanobiotechnol., 21.","DOI":"10.1186\/s12951-023-01973-5"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1021\/acsami.2c20728","article-title":"An Effective Peptide-Based Platform for Efficient Exosomal Loading and Cellular Delivery of a microRNA","volume":"15","author":"Hade","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1021\/acsami.3c10350","article-title":"Significant Enhancement of Fibroblast Migration, Invasion, and Proliferation by Exosomes Loaded with Human Fibroblast Growth Factor 1","volume":"16","author":"Hade","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2017.07.011","article-title":"Macrophage Exosomes as Natural Nanocarriers for Protein Delivery to Inflamed Brain","volume":"142","author":"Yuan","year":"2017","journal-title":"Biomaterials"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jconrel.2018.08.035","article-title":"Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson\u2019s disease","volume":"287","author":"Qu","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Bullock, K.M., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2020). Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124407"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12987-022-00359-3","article-title":"Extracellular vesicles through the blood\u2013brain barrier: A review","volume":"19","author":"Polakovicova","year":"2022","journal-title":"Fluids Barriers CNS"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"8129","DOI":"10.7150\/thno.62069","article-title":"Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer\u2019s disease-like phenotypes in a preclinical mouse model","volume":"11","author":"Cone","year":"2021","journal-title":"Theranostics"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"E3536","DOI":"10.1073\/pnas.1703920114","article-title":"Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus","volume":"114","author":"Long","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4103\/1673-5374.198966","article-title":"Emerging potential of exosomes for treatment of traumatic brain injury","volume":"12","author":"Xiong","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neuint.2016.08.003","article-title":"Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury","volume":"111","author":"Zhang","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/stem.1129","article-title":"Exosome-Mediated Transfer of miR-133b from Multipotent Mesenchymal Stromal Cells to Neural Cells Contributes to Neurite Outgrowth","volume":"30","author":"Xin","year":"2012","journal-title":"Stem Cells"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Liu, Q., Li, D., Pan, X., and Liang, Y. (2023). Targeted therapy using engineered extracellular vesicles: Principles and strategies for membrane modification. J. Nanobiotechnol., 21.","DOI":"10.1186\/s12951-023-02081-0"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Frolova, L., and Li, I.T.S. (2022). Targeting Capabilities of Native and Bioengineered Extracellular Vesicles for Drug Delivery. Bioengineering, 9.","DOI":"10.3390\/bioengineering9100496"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/24\/2100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:54:45Z","timestamp":1760115285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/24\/2100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,18]]},"references-count":109,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["cells13242100"],"URL":"https:\/\/doi.org\/10.3390\/cells13242100","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,18]]}}}