{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:33:47Z","timestamp":1777718027739,"version":"3.51.4"},"reference-count":6,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:00:00Z","timestamp":1598572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Covance Preclinical Services GmbH"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:p>Many potential drugs for treatment of neurodegenerative diseases, particularly antisense oligonucleotides (ASOs), are administered via lumbar intrathecal injection, because these drugs do not cross the blood\u2013brain barrier. Intrathecal injection is a well-established method in cynomolgus monkeys, a species that is used in preclinical safety assessment when other nonrodent species cannot be used. The authors completed intrathecal ASO administration in over 30 preclinical safety studies (&gt;1000 animals and &gt;4500 dose administrations) during which we observed 3 cases of procedure-related spinal cord necrosis (incidence &lt;0.1%). We describe clinical symptoms, diagnostic approaches, morphological features, and prognosis of this rare injury, and compare these findings with typical drug-related findings of ASOs dosed by intrathecal injection. The low incidence of procedure-related and dose-limiting lesions confines this analysis to a small sample set. The pattern of effects is similar across all monkeys despite differences in age, body weight, and intrathecal injection site. All 3 cases presented a combination of the following findings: blood in cerebrospinal fluid at time of injection, clinical signs that increase in severity within a day of dosing, lameness of both hind limbs, reduced muscle tone, and loss of patellar, foot grip, and\/or anal reflexes. In all cases, magnetic resonance imaging (MRI) showed a linear hyperintense lesion in the lumbar spinal cord. In 2 cases, this hyperintensity was associated with evidence of spinal cord edema. We conclude that a pattern of in-life and pathology findings, including noninvasive MRI assessment, is indicative of procedure-related effects.<\/jats:p>","DOI":"10.1177\/1091581820951098","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T06:00:47Z","timestamp":1598594447000},"page":"510-517","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Save Your Maximum Tolerated Dose: How to Diagnose Procedure-Related Spinal Cord Lesions After Lumbar Intrathecal Bolus Administration of Oligonucleotides in Cynomolgus Monkeys"],"prefix":"10.1177","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4151-9664","authenticated-orcid":false,"given":"Sven","family":"Korte","sequence":"first","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Luft","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"von Keutz","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Runge","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Mecklenburg","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7436-2432","authenticated-orcid":false,"given":"Magdalena Maria","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Department of Pediatric Radiology, Medical University of Lublin, Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serge","family":"Zander","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian Timo","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betina","family":"Pajaziti","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette","family":"Romeike","sequence":"additional","affiliation":[{"name":"Covance Preclinical Services GmbH, M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Korytko","sequence":"additional","affiliation":[{"name":"Preclinical GPS, Bainbridge Island, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"bibr1-1091581820951098","doi-asserted-by":"publisher","DOI":"10.1177\/1756286418776932"},{"key":"bibr2-1091581820951098","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99081"},{"key":"bibr3-1091581820951098","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000594"},{"key":"bibr4-1091581820951098","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A1567"},{"key":"bibr5-1091581820951098","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2012.03676.x"},{"key":"bibr6-1091581820951098","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-009-1539-7"}],"container-title":["International Journal of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581820951098","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1091581820951098","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1091581820951098","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:24:02Z","timestamp":1777458242000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/1091581820951098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,28]]},"references-count":6,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["10.1177\/1091581820951098"],"URL":"https:\/\/doi.org\/10.1177\/1091581820951098","relation":{},"ISSN":["1091-5818","1092-874X"],"issn-type":[{"value":"1091-5818","type":"print"},{"value":"1092-874X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,28]]}}}