{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:26Z","timestamp":1787005766705,"version":"build-2736575974"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the NIH","doi-asserted-by":"publisher","award":["T32GM007753"],"award-info":[{"award-number":["T32GM007753"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","award":["Sponsored Research Agreement"],"award-info":[{"award-number":["Sponsored Research Agreement"]}],"id":[{"id":"10.13039\/100005614","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":[[2024,12,3]]},"abstract":"<jats:p>Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrated that selective spinal cord expression driven by this mouse CRE is preserved in non-human primates. These findings suggest that cell-type-selective viral reagents in which cell-type-selective CREs drive restricted gene expression will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans.<\/jats:p>","DOI":"10.1073\/pnas.2418024121","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:13:52Z","timestamp":1732709632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Cis-regulatory elements driving motor neuron-selective viral payload expression within the mammalian spinal cord"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4608-1152","authenticated-orcid":false,"given":"M. Aurel","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"},{"name":"Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer","family":"Price","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"},{"name":"Department of Immunology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Gill","sequence":"additional","affiliation":[{"name":"Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna","family":"Jayne","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Pajak","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Deighan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Lu","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aissatou","family":"Diallo","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ching","family":"Lo","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Kleiman","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Henderson","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghae","family":"Suh","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0428-3215","authenticated-orcid":false,"given":"Eric C.","family":"Griffith","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-2160","authenticated-orcid":false,"given":"Michael E.","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinisa","family":"Hrvatin","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00293"},{"key":"e_1_3_4_2_2","volume-title":"StatPearls","author":"Arora R. D.","year":"2024","unstructured":"R. D. Arora, Y. S. Khan, \u201cMotor neuron disease\u201d in StatPearls (StatPearls Publishing, 2024)."},{"key":"e_1_3_4_3_2","article-title":"Gene therapy for spinal muscular atrophy (SMA): A review of current challenges and safety considerations for Onasemnogene Abeparvovec (Zolgensma)","volume":"15","author":"Ogbonmide T.","year":"2023","unstructured":"T. Ogbonmide , Gene therapy for spinal muscular atrophy (SMA): A review of current challenges and safety considerations for Onasemnogene Abeparvovec (Zolgensma). Cureus 15, e36197 (2023).","journal-title":"Cureus"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-12535-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.121"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.182698"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.05.040"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.157"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-021-01107-6"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01845-0"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01929-x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2023.29251.bfs"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba9188"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2020.167"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2005056"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.015"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407976101"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.03.032"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7742(03)01004-3"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.170"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4430"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.48089"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108754"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.03.011"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0692-9"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.69479"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2020.01.009"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.05.018"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.01.010"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33022-4"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.003"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22691-2"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25125-1"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.11.037"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","unstructured":"M. A. Nagy M. E. Greenberg S. Hrvatin Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE278180. Deposited 26 September 2024.","DOI":"10.1101\/2024.09.02.610875"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0209-0"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_3_4_38_2","first-page":"29.1","article-title":"ATAC-seq: A method for assaying chromatin accessibility genome-wide","volume":"109","author":"Buenrostro J. D.","year":"2015","unstructured":"J. D. Buenrostro, B. Wu, H. Y. Chang, W. J. Greenleaf, ATAC-seq: A method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 29.1\u201321.29.9 (2015).","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.136184.111"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.018"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2016.60"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2022.03.017"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.975803"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003179"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.52.33358"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.9.4046"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.12.032"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr064"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0225206"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12050785"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2015.55"},{"key":"e_1_3_4_54_2","unstructured":"E. Kussick Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque. bioRxiv [Preprint] (2024). https:\/\/www.biorxiv.org\/content\/10.1101\/2024.07.30.605864v1 (Accessed 1 November 2024)."},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302676110"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1067020"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31868-8"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44321-024-00036-y"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1143157"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00827-3"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821000116"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.02.007"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2418024121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:17:03Z","timestamp":1732709823000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2418024121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":62,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2024,12,3]]}},"alternative-id":["10.1073\/pnas.2418024121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2418024121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]},"assertion":[{"value":"2024-09-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2418024121"}}