{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:51:16Z","timestamp":1790783476060,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"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>Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. Gene therapy may offer an efficient method to ameliorate the symptoms of this disorder. Methods An AAVphp.eb-hSyn-mFMR1IOS7 vector and an empty control were injected into the tail vein of adult Fmr1 knockout (KO) mice and wildtype (WT) controls. The KO mice were injected with 2 \u00d7 1013 vg\/kg of the construct. The control KO and WT mice were injected with an empty vector. Four weeks following treatment, the animals underwent a battery of tests: open field, marble burying, rotarod, and fear conditioning. The mouse brains were studied for levels of the Fmr1 product FMRP. Results: No significant levels of FMRP were found outside the CNS in the treated animals. The gene delivery was highly efficient, and it exceeded the control FMRP levels in all tested brain regions. There was also improved performance in the rotarod test and partial improvements in the other tests in the treated KO animals. Conclusion: These experiments demonstrate efficient, brain-specific delivery of Fmr1 via peripheral administration in adult mice. The gene delivery led to partial alleviation of the Fmr1 KO phenotypical behaviors. FMRP oversupply may explain why not all behaviors were significantly affected. Since AAV.php vectors are less efficient in humans than in the mice used in the current experiment, studies to determine the optimal dose using human-suitable vectors will be necessary to further demonstrate feasibility.<\/jats:p>","DOI":"10.3390\/genes14020505","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T02:27:24Z","timestamp":1676600844000},"page":"505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["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"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-7225","authenticated-orcid":false,"given":"Kathryn K.","family":"Chadman","sequence":"first","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Adayev","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Udayan","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"},{"name":"Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5079-6156","authenticated-orcid":false,"given":"Rida","family":"Ahmed","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"},{"name":"Macaulay Honors College at Hunter CUNY, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-142X","authenticated-orcid":false,"given":"Chun-Ling","family":"Dai","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Goodman","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"},{"name":"Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Meeker","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Dolzhanskaya","sequence":"additional","affiliation":[{"name":"NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0551-2019","authenticated-orcid":false,"given":"Milen","family":"Velinov","sequence":"additional","affiliation":[{"name":"Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/hmg\/5.6.727","article-title":"Population screening at the FRAXA and FRAXE loci: Molecular analyses of boys with learning difficulties and their mothers","volume":"5","author":"Murray","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/ajmg.10427","article-title":"Prevalence of the fragile X syndrome in African Americans","volume":"110","author":"Crawford","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/nn.2563","article-title":"Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack","volume":"13","author":"Brown","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.neuron.2012.12.018","article-title":"FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels","volume":"77","author":"Deng","year":"2013","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1038\/ncomms4628","article-title":"Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density","volume":"5","author":"Ferron","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0092-8674(01)00568-2","article-title":"Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome","volume":"107","author":"Brown","year":"2001","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fyke, W., and Velinov, M. (2021). FMR1 and Autism, an Intriguing Connection Revisited. Genes, 12.","DOI":"10.3390\/genes12081218"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1542\/peds.2008-0317","article-title":"Advances in the treatment of fragile X syndrome","volume":"123","author":"Hagerman","year":"2009","journal-title":"Pediatrics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s11689-017-9184-y","article-title":"Acamprosate in a mouse model of fragile X syndrome: Modulation of spontaneous cortical activity, ERK1\/2 activation, locomotor behavior, and anxiety","volume":"9","author":"Schaefer","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2174\/1573396315666190625110748","article-title":"New Targeted Treatments for Fragile X Syndrome","volume":"15","author":"Protic","year":"2019","journal-title":"Curr. Pediatr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Erickson, C.A., Kaufmann, W.E., Budimirovic, D.B., Lachiewicz, A., Haas-Givler, B., Miller, R.M., Weber, J.D., Abbeduto, L., Hessl, D., and Hagerman, R.J. (2018). Best Practices in Fragile X Syndrome Treatment Development. Brain Sci., 8.","DOI":"10.3390\/brainsci8120224"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hampson, D.R., Hooper, A.W.M., and Niibori, Y. (2019). The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome. Brain Sci., 9.","DOI":"10.3390\/brainsci9020032"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1038\/nn.4593","article-title":"Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems","volume":"20","author":"Chan","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.omtm.2018.07.006","article-title":"Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65","volume":"10","author":"Hudry","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aslesh, T., and Yokota, T. (2022). Restoring SMN Expression: An Overview of the Therapeutic Developments for the Treatment of Spinal Muscular Atrophy. Cells, 11.","DOI":"10.3390\/cells11030417"},{"key":"ref_16","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_17","unstructured":"Velinov, M., Ling Dai, C., Merz, G., Wise, T., Goodman, J., Meeker, H., Adayev, T., and Dolzhanskaya, N. (2023, February 01). Efficient Delivery of FMR1 across the Blood Brain Barrier Using AAVphp Construct-Feasibility of Gene Therapy for Fragile X syndrome. (Abstract # 2636) Presented at the 71 Virtual Annual Meeting of the American Society of Human Genetics, 20 October 2021. Available online: https:\/\/www.researchgate.net\/publication\/355788640_Efficient_Delivery_of_FMR1_across_the_blood_brain_barrier_using_AAVphp_construct-feasibility_of_gene_therapy_for_Fragile_X_syndrome."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16081","DOI":"10.1038\/mtm.2016.81","article-title":"Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9","volume":"3","author":"Dashkoff","year":"2016","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1002\/aur.2520","article-title":"Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-\u03b1, induces autism spectrum disorder-like and co-morbid phenotypes in adult C57BL","volume":"14","author":"Fyke","year":"2021","journal-title":"J. Mice. Autism. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/978-981-13-8023-5_76","article-title":"Taurine Partially Improves Abnormal Anxiety in Taurine-Deficient Mice","volume":"1155","author":"Park","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1523\/JNEUROSCI.2010-17.2017","article-title":"Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice","volume":"38","author":"Steinmetz","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Adayev, T., LaFauci, G., Xu, W., Dobkin, C., Kascsak, R., Brown, W.T., and Goodman, J.H. (2021). Development of a Quantitative FMRP Assay for Mouse Tissue Applications. Genes, 12.","DOI":"10.3390\/genes12101516"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1038\/s41467-020-16250-4","article-title":"FMRP(1-297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome","volume":"11","author":"Zhan","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.brainres.2014.11.023","article-title":"Expression of Fragile X Mental Retardation Protein in Neurons and Glia of the Developing and Adult Mouse Brain","volume":"1596","author":"Gholizadeh","year":"2015","journal-title":"Brain Res."},{"key":"ref_26","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":"Yiru","year":"2022","journal-title":"Mol. Therapy. Methods Clin. Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109234","DOI":"10.1016\/j.neuropharm.2022.109234","article-title":"Agmatine relieves behavioral impairments in Fragile X mice model","volume":"219","author":"Jeon","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fncel.2014.00070","article-title":"2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice","volume":"8","author":"Gandhi","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/ejhg.2012.78","article-title":"De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity","volume":"20","author":"Vengoechea","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10048-012-0340-y","article-title":"Small genomic rearrangements involving FMR1 support the importance of its gene dosage for normal neurocognitive function","volume":"13","author":"Nagamani","year":"2012","journal-title":"Neurogenetics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.omtm.2020.10.011","article-title":"CNS Transduction Benefits of AAV-PHP.eB over AAV9 Are Dependent on Administration Route and Mouse Strain","volume":"19","author":"Mathiesen","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Huang, Q., Chan, K.Y., Tobey, I.G., Chan, Y.A., Poterba, T., Boutros, C.L., Balazs, A.B., Daneman, R., and Bloom, J.M. (2019). Delivering Genes across the Blood-Brain Barrier: LY6A, a Novel Cellular Receptor for AAV-PHP.B Capsids. PLoS ONE, 14, Available online: https:\/\/journals.plos.org\/plosone\/article?id=10.1371\/journal.pone.0225206.","DOI":"10.1101\/538421"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1095\/biolreprod.105.040303","article-title":"LY6A\/E (SCA-1) expression in the mouse testis","volume":"73","author":"Ciliberti","year":"2005","journal-title":"Biol. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1111\/ejn.14660","article-title":"Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons","volume":"51","author":"Graef","year":"2020","journal-title":"Eur. J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1002\/ajmg.a.62594","article-title":"The association between mosaicism type and cognitive and behavioral functioning among males with fragile X syndrome","volume":"188","author":"Meng","year":"2022","journal-title":"Am. J. Med. Genet. A."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:38:23Z","timestamp":1760121503000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020505"],"URL":"https:\/\/doi.org\/10.3390\/genes14020505","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]}}}