Juvenile Göttingen minipigs as pediatric safety testing model for antisense oligonucleotides (ASOs)
Antisense oligonucleotides (ASOs) belong to a large group of nucleic acid-based therapeutics that utilize synthetic oligonucleotides to modulate RNA translation. As ASOs need to hybridize to their complementary target RNA, nonhuman primates (NHPs) are the preferred non-rodent model due to their close genetic homology and pharmacokinetics with humans. However, the adult Göttingen Minipig has been recognized as a suitable alternative to NHPs in the safety testing of ASOs, as it showed similar pharmacokinetic, pharmacodynamic, and safety profiles in a previous study. Since ASOs are usually indicated to rare genetic conditions that could start early in life, and as the rapid growth and development of the pediatric population can influence the pharmacokinetics/pharmacodynamics of therapeutic agents, leading to potential toxicities, extending the previous work to the juvenile minipigs was deemed necessary. In this thesis, we evaluated the juvenile Göttingen Minipig as a pediatric safety testing model for ASOs. As such, we assessed potential differences in exposure/toxicity and pharmacologic effect of a model ASO (RTR5001) in the juvenile Göttingen Minipig in an 8-week repeat-dose toxicity study (weekly subcutaneous dosing starting at postnatal day 1). Accordingly, the model ASO that had been previously characterized in adult Göttingen Minipigs and NHPs showed comparable clinical chemistry and toxicity profiles in the juvenile minipigs. However, differences in plasma and tissue exposures, and pharmacologic activity were observed compared to the adult data. The ontogeny evaluation of the key nucleases responsible for ASO metabolism and pharmacologic activity revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. Likewise, to further understand the species translatability of ASO-induced thrombocytopenia, in vitro platelet activity and aggregometry assays were performed using a panel of tool ASOs with different sequences and modifications. Our data on direct platelet activation and aggregation by ASOs in adult minipig samples are remarkably comparable to human data. Moreover, phosphorothioated ASOs bind to platelet collagen receptor glycoprotein VI (GPVI) and directly activate minipig platelets in vitro, mirroring the findings in human samples. The differential abundance of GPVI (and platelet factor 4) in minipigs provides insight into the influence of ontogeny in potential ASO-induced thrombocytopenia in pediatrics. Therefore, the body of data from this thesis is fundamental for selecting the juvenile Göttingen Minipig in assessing safety concerns for ASOs intended for the human pediatric population.
Antwerp : University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Veterinary Sciences , 2023
217 p.
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Creation 26.10.2023
Last edited 26.11.2023
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