Peters, Sebastian and Wirkert, Eva and Kuespert, Sabrina and Heydn, Rosmarie and Korte, Sven and Mecklenburg, Lars and Aigner, Ludwig and Johannesen, Siw and Bruun, Tim-Henrik and Bogdahn, Ulrich (2022) Targeting TGF-ss in the Central Nervous System: Assessment of Cynomolgus Monkey-Toxicity and Pharmacokinetics for an LNA-Antisense Oligonucleotide. APPLIED SCIENCES-BASEL, 12 (3): 973. ISSN 2076-3417
Full text not available from this repository.Abstract
Increasingly antisense oligonucleotides (ASOs) are developed for potential treatment of CNS disorders, and due to the inability to cross the blood brain barrier, they require direct administration into the cerebrospinal fluid (CSF). In this regard, intrathecal (i.th.) administration in cynomolgus monkeys (Macaca fascicularis) is a well-established approach for preclinical safety studies. Here, we present an innovative preclinical approach that is intended to support rapid entry into clinical development with ASOs targeting the CNS. The preclinical approach comprises one non-GLP study in 26 non-human primates, followed by a pivotal GLP repeated dose toxicity study in the same species. No pivotal rodent studies were conducted, and regulatory guidance to initiate this study was met by in vitro work. The non-GLP study consists of three separate phases: Phase A determines toxicity after i.th. administrations with five escalating dose levels in a single male and female animal, respectively. Dosing is conducted on days 1, 8, 15, 22, and 29 and the experiment is terminated 36 days after start of the study. The second phase (Phase B) investigates pharmacokinetics over a 2- or 4-week period at two dose levels following single administrations in eight (8) animals (4 females, 4 males). Finally, a third phase (Phase C) investigates toxicity and pharmacokinetics after repeated (9x) dosing over a 13-week period at two dose levels in sixteen (8 females, 8 males) animals. In each phase, clinical observations and physical/neurological parameters are investigated directly pre-dose, 4 h and 24 h post-dose, respectively. In all phases, CSF and blood samples are taken pre-dose and after each dosing, for determination of test article concentration, biomarkers of tolerability and biomarkers of pharmacology. In all phases, tissue samples from the liver, kidney, spinal cord, and brain are collected for determination of NVP-13 tissue concentrations. The above concept has successfully supported first-in-human clinical trials. The entire non-GLP program is completed within less than six months and requires fewer animals in comparison to the conduct of three independent studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BETA; NEURODEGENERATION; INHIBITION; THERAPIES; antisense oligonucleotide therapy; LNA; TGFss-signaling; neurodegeneration; ALS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Feb 2024 06:49 |
| Last Modified: | 08 Feb 2024 06:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57382 |
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