2020
DOI: 10.1177/1091581820951098
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Save Your Maximum Tolerated Dose: How to Diagnose Procedure-Related Spinal Cord Lesions After Lumbar Intrathecal Bolus Administration of Oligonucleotides in Cynomolgus Monkeys

Abstract: 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–brain 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 (>1000 animals and >… Show more

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Cited by 4 publications
(12 citation statements)
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“…administration [44]. A recently published paper by Korte et al described these effects as not necessarily ASO-related, since they also occurred in aCSF-treated animals, indicating the dosing procedure per se influences neurological parameters [45]. Further, persistent loss of one or more reflexes was described as non-adverse, since no fundamental physiological deficit or behavioral alterations were noted [44].…”
Section: Discussionmentioning
confidence: 99%
“…administration [44]. A recently published paper by Korte et al described these effects as not necessarily ASO-related, since they also occurred in aCSF-treated animals, indicating the dosing procedure per se influences neurological parameters [45]. Further, persistent loss of one or more reflexes was described as non-adverse, since no fundamental physiological deficit or behavioral alterations were noted [44].…”
Section: Discussionmentioning
confidence: 99%
“…For example, while ASO class-related effects are typically transient (usually persisting for 4 to no more than 24 hours after dosing), adverse procedure-related effects are more likely to persist beyond 24 hours after dosing. 17,18 The IT bolus injection procedure for NHPs has been previously described 17,18 and is similar to the details described above for the dog. Briefly, sedated animals are placed in sternal recumbency on a curved metal grid with the arms fixed with slings to prevent movement (Figure 1A-D).…”
Section: Nonhuman Primates-intrathecal Injectionmentioning
confidence: 99%
“…are generally documented twice daily during the dosing phase while neurological examinations (behaviors, reflexes, etc.) are generally performed prior to each dose and at 4 hours post-dose, potentially followed by a functional observational battery (FOB) 14,15,19,22 or modified Irwin test 15,19 (i.e., multi-assay batteries that assess core autonomic, behavioral, neuromuscular, and sensorimotor functions) in the 17,18 ). rare case that severe clinical and/or neurological abnormalities, such as severe ataxia, are observed.…”
Section: Procedure-related Functional Effects Of Direct Cns Deliverymentioning
confidence: 99%
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“…Due to the inability to cross the blood brain barrier, ASOs require direct administration into the cerebrospinal fluid (CSF): i.th. bolus delivery in cynomolgus monkeys is a preferred method in preclinical safety assessment of central nervous system (CNS) drugs [23,24]. Occasionally, port-catheterization is preferred for overcoming some more specific pharmacokinetic limitations [25][26][27].…”
Section: Introductionmentioning
confidence: 99%