{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:30:20Z","timestamp":1793313020775,"version":"4.5.0"},"reference-count":48,"publisher":"American Society for Clinical Investigation","issue":"20","funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013669","name":"Ionis Pharmaceuticals","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100013669","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,17]]},"abstract":"<jats:p>\n                    Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs. Following lumbar IT bolus injection in rats, all ASOs spread rostrally along the neuraxis, adhered to meninges, and were partially cleared to peripheral lymph nodes and kidneys. Rapid association with the pia and arterial walls preceded passage of ASOs across the glia limitans, along arterial intramural basement membranes, and along white-matter axonal bundles. Several neuronal and glial cell types accumulated ASOs over time, with evidence of probable glial accumulation preceding neuronal uptake. IT doses of anti-\n                    <jats:italic>GluR1<\/jats:italic>\n                    and anti-\n                    <jats:italic>Gabra1<\/jats:italic>\n                    ASOs markedly reduced the mRNA and protein levels of their respective neurotransmitter receptor protein targets by 2 weeks and anti-\n                    <jats:italic>Gabra1<\/jats:italic>\n                    ASOs also reduced binding of the GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor PET ligand\n                    <jats:sup>18<\/jats:sup>\n                    F-flumazenil in the brain over 4 weeks. Our multimodal imaging approaches elucidate multiple transport routes underlying the CNS distribution, clearance, and efficacy of IT-dosed ASOs.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.129240","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T11:04:18Z","timestamp":1571223858000},"source":"Crossref","is-referenced-by-count":125,"title":["Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging"],"prefix":"10.1172","volume":"4","author":[{"given":"Curt","family":"Mazur","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berit","family":"Powers","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Zasadny","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna M.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."},{"name":"Biogen, Cambridge, Masschusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-7873","authenticated-orcid":true,"given":"Hemi","family":"Dimant","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Kamme","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Hesterman","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Matson","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Oestergaard","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Seaman","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Holt","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Qutaish","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildiko","family":"Polyak","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Coelho","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Gottumukkala","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolynn M.","family":"Gaut","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Berridge","sequence":"additional","affiliation":[{"name":"3D Imaging, Little Rock, Arkansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1435-8612","authenticated-orcid":true,"given":"Nazira J.","family":"Albargothy","sequence":"additional","affiliation":[{"name":"University of Southampton, Hampshire, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Kelly","sequence":"additional","affiliation":[{"name":"University of Southampton, Hampshire, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana O.","family":"Carare","sequence":"additional","affiliation":[{"name":"University of Southampton, Hampshire, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Hoppin","sequence":"additional","affiliation":[{"name":"Invicro, LLC, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Kordasiewicz","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric E.","family":"Swayze","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Verma","sequence":"additional","affiliation":[{"name":"Biogen, Cambridge, Masschusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,10,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-9124-0"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31408-8"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.09.001"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-013-0194-5"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-018-0409-9"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(17)30087-1"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2018.1416089"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/58.3.292"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/BF00265844"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aeh204"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1812-4"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1862-7"},{"issue":"147","key":"B13","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci Transl Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.119"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00042.2016"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2010.053157"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005761031077"},{"issue":"3","key":"B18","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrn.2015.29","article-title":"Extracellular vesicles round off communication in the nervous system","volume":"17","author":"Budnik","year":"2016","journal-title":"Nat Rev Neurosci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12042"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/0165-5728(89)90136-7"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01484-6"},{"issue":"3","key":"B22","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/BF00239012","article-title":"Morphological indications for considerable diffuse reabsorption of cerebrospinal fluid in spinal meninges particularly in the areas of meningeal funnels. An electronmicroscopical study including tracing experiments in rats","volume":"189","author":"Zenker","year":"1994","journal-title":"Anat Embryol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/BF00309843"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1679\/aohc.61.277"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142290"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature14432"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2019.00001","article-title":"Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain","volume":"11","author":"Aldea","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-012-0073-3"},{"issue":"2","key":"B29","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.85311","article-title":"Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery","volume":"1","author":"Wolf","year":"2016","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aar3959"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1722344115"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25118"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2017.02.001"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2013.0443"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.009"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99081"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1260"},{"issue":"3","key":"B38","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/S0022-3565(24)38831-7","article-title":"Pharmacokinetic properties of 2\u2032-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats","volume":"296","author":"Geary","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"B39"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.212407"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31408-8"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aap8677"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1364\/AO.28.004930"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2002.5576"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1364\/AO.28.004930"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/ar.20849"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-009-9726-x"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2004.11.001"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/129240\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:22:36Z","timestamp":1779193356000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/129240"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,17]]},"references-count":48,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10,17]]},"published-print":{"date-parts":[[2019,10,17]]}},"alternative-id":["10.1172\/jci.insight.129240"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.129240","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,17]]},"article-number":"e129240"}}