{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:16:06Z","timestamp":1784772966129,"version":"3.55.0"},"reference-count":55,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T00:00:00Z","timestamp":1659916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["NS110868"],"award-info":[{"award-number":["NS110868"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016499","name":"Rett Syndrome Research Trust","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100016499","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,8,16]]},"abstract":"<jats:p>\n                    Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editase\n                    <jats:sup>wt<\/jats:sup>\n                    ) and either\n                    <jats:italic>Mecp2<\/jats:italic>\n                    -targeting or nontargeting\n                    <jats:italic>gfp<\/jats:italic>\n                    RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the\n                    <jats:italic>Mecp2<\/jats:italic>\n                    -targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the\n                    <jats:italic>Mecp2<\/jats:italic>\n                    -targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control\n                    <jats:italic>gfp<\/jats:italic>\n                    guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editase\n                    <jats:sup>wt<\/jats:sup>\n                    . Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2206053119","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T15:16:07Z","timestamp":1659971767000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":41,"title":["Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6818-9389","authenticated-orcid":false,"given":"John R.","family":"Sinnamon","sequence":"first","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Yung","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna R.","family":"Fisk","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Jeng","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8333-6607","authenticated-orcid":false,"given":"Shannon K.","family":"McWeeney","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239"},{"name":"Division of Bioinformatics and Computational Biology, Oregon Health and Science University, Portland, OR 97239"},{"name":"Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR 97239"},{"name":"Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay K.","family":"Parmelee","sequence":"additional","affiliation":[{"name":"Integrated Pathology Core, Oregon National Primate Research Center, Beaverton, OR 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-9481","authenticated-orcid":false,"given":"Chi Ngai","family":"Chan","sequence":"additional","affiliation":[{"name":"Integrated Pathology Core, Oregon National Primate Research Center, Beaverton, OR 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2427-401X","authenticated-orcid":false,"given":"Siu-Pok","family":"Yee","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-4516","authenticated-orcid":false,"given":"Gail","family":"Mandel","sequence":"additional","affiliation":[{"name":"Vollum Institute, Oregon Health and Science University, Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,8,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-020-00272-5"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/1566523220666200516170137"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1306243110"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060208-105251"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.48.4.613"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07321-8"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1163"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2015.4"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.18.8298"},{"key":"e_1_3_4_10_2","first-page":"2797","article-title":"Harnessing human ADAR2 for RNA repair\u2014Recoding a PINK1 mutation rescues mitophagy","volume":"45","author":"Wettengel J.","year":"2017","unstructured":"J. Wettengel, P. Reautschnig, S. Geisler, P. J. Kahle, T. Stafforst, Harnessing human ADAR2 for RNA repair\u2014Recoding a PINK1 mutation rescues mitophagy. Nucleic Acids Res. 45, 2797\u20132808 (2017).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep41478"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0013-6"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01105-0"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0178-z"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01180-3"},{"key":"e_1_3_4_16_2","first-page":"e157","article-title":"An efficient system for selectively altering genetic information within mRNAs","volume":"44","author":"Montiel-Gonz\u00e1lez M. F.","year":"2016","unstructured":"M. F. Montiel-Gonz\u00e1lez, I. C. Vallecillo-Viejo, J. J. Rosenthal, An efficient system for selectively altering genetic information within mRNAs. Nucleic Acids Res. 44, e157 (2016).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1715320114"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaq0180"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0017-z"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0323-0"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1212548109"},{"key":"e_1_3_4_22_2","first-page":"98","volume-title":"Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders","author":"Kilstrup-Nielsen C.","year":"2015","unstructured":"C. Kilstrup-Nielsen, N. Landsberger, \u201cRett syndrome: From the involved gene(s) to treatment\u201d in Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, M. J. Zigmond, L. P. Rowland, J. T. Coyle, Eds. (Academic Press, 2015), pp. 98\u2013119."},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22124"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000223318.28938.45"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1177\/08830738030180100301"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.10.004"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30217-9"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/30764"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/20.19.5085"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107878"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2017.1387711"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1324"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1017\/S135583820101007X"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81887-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006793"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618737114"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.01.030"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.2.115"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10214"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1873-2"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02287-1"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.10.011"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01171-4"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01225-1"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2013.06.022"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-040510-130049"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.12.009"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.12.022"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-06-2501"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv496"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24058"},{"key":"e_1_3_4_55_2","unstructured":"J. R. Sinnamon Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome. Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/sra\/?term=PRJNA849938. Deposited 1 August 2021."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2206053119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T15:20:59Z","timestamp":1659972059000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2206053119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,8]]},"references-count":55,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2022,8,16]]}},"alternative-id":["10.1073\/pnas.2206053119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2206053119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,8]]},"assertion":[{"value":"2022-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2206053119"}}