{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:29:55Z","timestamp":1789414195608,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vaccinex Ltd","award":["1"],"award-info":[{"award-number":["1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A\/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A\/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A\/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D\u2013Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.<\/jats:p>","DOI":"10.3390\/ijms22179465","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T08:42:32Z","timestamp":1630399352000},"page":"9465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3573-6486","authenticated-orcid":false,"given":"Yilin","family":"Mao","sequence":"first","affiliation":[{"name":"Molecular Neurobiology Research Laboratory, Kids Neuroscience Centre, Kids Research, The Children\u2019s Hospital at Westmead, Westmead, NSW 2145, Australia"},{"name":"Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Evans","sequence":"additional","affiliation":[{"name":"Vaccinex Inc., Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Mishra","sequence":"additional","affiliation":[{"name":"Vaccinex Inc., Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Balch","sequence":"additional","affiliation":[{"name":"Vaccinex Inc., Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Vaccinex Inc., Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Zauderer","sequence":"additional","affiliation":[{"name":"Vaccinex Inc., Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1808-0646","authenticated-orcid":false,"given":"Wendy","family":"Gold","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Research Laboratory, Kids Neuroscience Centre, Kids Research, The Children\u2019s Hospital at Westmead, Westmead, NSW 2145, Australia"},{"name":"Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"},{"name":"Molecular Neurobiology Research Laboratory, The Children\u2019s Medical Research Institute, Westmead, NSW 2145, Australia"},{"name":"School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1016\/S0387-7604(01)00356-4","article-title":"Sleep dysfunction in Rett syndrome: Lack of age related decrease in sleep duration","volume":"23","author":"Ellaway","year":"2001","journal-title":"Brain Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jpeds.2005.10.037","article-title":"Rett syndrome in Australia: A review of the epidemiology","volume":"148","author":"Laurvick","year":"2006","journal-title":"J. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7951","DOI":"10.1523\/JNEUROSCI.0169-11.2011","article-title":"Complexities of Rett Syndrome and MeCP2","volume":"31","author":"Samaco","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.nbd.2015.05.005","article-title":"Unexpected cellular players in Rett syndrome pathology","volume":"92","author":"Cronk","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"316","DOI":"10.3389\/fnmol.2017.00316","article-title":"MeCP2 Deficiency in Neuroglia: New Progress in the Pathogenesis of Rett Syndrome","volume":"10","author":"Jin","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5051","DOI":"10.1523\/JNEUROSCI.0324-09.2009","article-title":"Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions","volume":"29","author":"Maezawa","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_7","first-page":"497","article-title":"A role for glia in the progression of Rett\u2019s syndrome","volume":"475","author":"Lioy","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/hmg\/ddv464","article-title":"Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes","volume":"25","author":"Delepine","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3389\/fncel.2015.00266","article-title":"The Utility of Next-Generation Sequencing in Gene Discovery for Mutation-Negative Patients with Rett Syndrome","volume":"9","author":"Gold","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Okabe, Y., Takahashi, T., Mitsumasu, C., Kosai, K.-I., Tanaka, E., and Matsuishi, T. (2012). Alterations of Gene Expression and Glutamate Clearance in Astrocytes Derived from an MeCP2-Null Mouse Model of Rett Syndrome. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035354"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuron.2011.03.001","article-title":"Experience-Dependent Retinogeniculate Synapse Remodeling Is Abnormal in MeCP2-Deficient Mice","volume":"70","author":"Noutel","year":"2011","journal-title":"Neuron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jneuroim.2015.04.005","article-title":"Methyl CpG binding protein 2 deficiency enhances expression of inflammatory cytokines by sustaining NF-\u03baB signaling in myeloid derived cells","volume":"283","author":"Lima","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.nbd.2014.10.008","article-title":"SEMA4D compromises blood\u2013brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease","volume":"73","author":"Smith","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.neuint.2009.05.013","article-title":"Involvement of Sema4D in the control of microglia activation","volume":"55","author":"Toguchi","year":"2009","journal-title":"Neurochem. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00011-016-0983-5","article-title":"Semaphorins 4A and 4D in chronic inflammatory diseases","volume":"66","author":"Chapoval","year":"2016","journal-title":"Inflamm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/s41380-018-0021-9","article-title":"Are immunotherapies for Huntington\u2019s disease a realistic option?","volume":"24","author":"Denis","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.nbd.2015.01.002","article-title":"Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease","volume":"76","author":"Southwell","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1517\/14728222.2016.1139083","article-title":"The role of Sema4D\/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases","volume":"20","author":"Wu","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1096\/fj.201700786RR","article-title":"Sema4D\/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats","volume":"32","author":"Zhou","year":"2018","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1158\/2326-6066.CIR-14-0171","article-title":"Antibody blockade of semaphorin 4D promotes immune infiltration into tumor and enhances response to other immunomodulatory therapies","volume":"3","author":"Evans","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/cyto.b.21338","article-title":"Saturation monitoring of VX15\/2503, a novel semaphorin 4D-specific antibody, in clinical trials","volume":"90","author":"Fisher","year":"2016","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"297","DOI":"10.4161\/mabs.23684","article-title":"Antibody biodistribution coefficients: Inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human","volume":"5","author":"Shah","year":"2012","journal-title":"mAbs"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wang, Q., Delva, L., Weinreb, P.H., Pepinsky, R.B., Graham, D., Veizaj, E., Cheung, A.E., Chen, W., Nestorov, I., and Rohde, E. (2018). Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration. Fluids Barriers CNS, 15.","DOI":"10.1186\/s12987-018-0093-6"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18267","DOI":"10.1073\/pnas.0608702103","article-title":"Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome","volume":"103","author":"McGill","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1002\/mds.22115","article-title":"Movement disorders in Rett syndrome: An analysis of 60 patients with detected MECP2 mutation and correlation with mutation type","volume":"23","author":"Temudo","year":"2008","journal-title":"Mov. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1002\/mds.22595","article-title":"Evolution of stereotypies in adolescents and women with Rett syndrome","volume":"24","author":"Vignoli","year":"2009","journal-title":"Mov. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nn.2997","article-title":"Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses","volume":"15","author":"Goffin","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hsu, W.L., Ma, Y.L., Liu, Y.C., Tai, D.J., and Lee, E.H. (2020). Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-57745-w"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhou, Z., and Goffin, D. (2014). Modeling Rett Syndrome with MeCP2 T158A Knockin Mice. Compr. Guide Autism, 2723\u20132739.","DOI":"10.1007\/978-1-4614-4788-7_181"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Anderson, A., Wong, K., Jacoby, P., Downs, J., and Leonard, H. (2014). Twenty years of surveillance in Rett syndrome: What does this tell us?. Orphanet J. Rare Dis., 9.","DOI":"10.1186\/1750-1172-9-87"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1111\/j.1460-9568.2008.06305.x","article-title":"Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndromeMecp2gene dosage effects and BDNF expression","volume":"27","author":"Kondo","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.neubiorev.2017.03.002","article-title":"Astrocytic modulation of neuronal excitability through K+ spatial buffering","volume":"77","author":"Morley","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kahanovitch, U., Patterson, K.C., Hernandez, R., and Olsen, M.L. (2019). Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20153813"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Pacheco, N.L., Heaven, M.R., Holt, L.M., Crossman, D.K., Boggio, K.J., Shaffer, S.A., Flint, D.L., and Olsen, M.L. (2017). RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome. Mol. Autism, 8.","DOI":"10.1186\/s13229-017-0174-4"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fncel.2013.00038","article-title":"Multifunctional role of astrocytes as gatekeepers of neuronal energy supply","volume":"7","author":"Stobart","year":"2013","journal-title":"Front. Cell. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhao, D., Mokhtari, R., Pedrosa, E., Birnbaum, R., Zheng, D., and Lachman, H.M. (2017). Transcriptome analysis of microglia in a mouse model of Rett syndrome: Differential expression of genes associated with microglia\/macrophage activation and cellular stress. Mol. Autism, 8.","DOI":"10.1186\/s13229-017-0134-z"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.resp.2009.04.017","article-title":"Breathing disorders in Rett syndrome: Progressive neurochemical dysfunction in the respiratory network after birth","volume":"168","author":"Katz","year":"2009","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1113\/JP270369","article-title":"Impaired CO2 sensitivity of astrocytes in a mouse model of Rett syndrome","volume":"593","author":"Turovsky","year":"2015","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C729","DOI":"10.1152\/ajpcell.00334.2010","article-title":"The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome","volume":"301","author":"Zhang","year":"2011","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.4049\/jimmunol.0903302","article-title":"Roles of Sema4D\u2013plexin-B1 interactions in the central nervous system for pathogenesis of experimental auto-immune encephalomyelitis","volume":"184","author":"Okuno","year":"2010","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1038\/s41467-020-15590-5","article-title":"P2X7 receptor inhibition ameliorates dendritic spine pathology and social behavioral deficits in Rett syndrome mice","volume":"11","author":"Silva","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/glia.22372","article-title":"Microglia as modulators of cognition and neuropsychiatric disorders","volume":"61","author":"Blank","year":"2013","journal-title":"Glia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1080\/19420862.2015.1102813","article-title":"Generation and preclinical characterization of an antibody specific for SEMA4D","volume":"8","author":"Fisher","year":"2016","journal-title":"mAbs"},{"key":"ref_44","first-page":"1152","article-title":"Modulation of RhoGTPases Improves the Behavioral Phenotype and Reverses Astrocytic Deficits in a Mouse Model of Rett Syndrome","volume":"37","author":"Fabbri","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bbr.2008.07.008","article-title":"Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp21lox mice","volume":"196","author":"Nag","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.neuroscience.2007.02.009","article-title":"Behavioral and anatomical abnormalities in Mecp2 mutant mice: A model for Rett syndrome","volume":"146","author":"Stearns","year":"2007","journal-title":"Neuroscience"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1212\/01.wnl.0000291011.54508.aa","article-title":"Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome","volume":"70","author":"Neul","year":"2008","journal-title":"Neurology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/ajmg.a.20571","article-title":"Phenotypic manifestations ofMECP2 mutations in classical and atypical rett syndrome","volume":"126A","author":"Schanen","year":"2004","journal-title":"Am. J. Med. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S246","DOI":"10.1016\/S0387-7604(01)00343-6","article-title":"MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: Hot spot map of the most re-current mutations and bioinformatic analysis of a new MECP2 conserved region","volume":"23","author":"Vacca","year":"2001","journal-title":"Brain Dev."},{"key":"ref_50","first-page":"e1088","article-title":"Elevated Plus Maze for Mice","volume":"2008","author":"Komada","year":"2008","journal-title":"J. Vis. Exp."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:26Z","timestamp":1760165606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,31]]},"references-count":50,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179465"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179465","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,31]]}}}