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Article

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

1
Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium
2
Charles River Laboratories France Safety Assessment SAS, 69210 Saint-Germain-Nuelles, France
3
Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Both authors contributed equally.
Academic Editor: José B. Fariña
Received: 27 July 2021 / Revised: 6 September 2021 / Accepted: 7 September 2021 / Published: 10 September 2021
(This article belongs to the Special Issue Development and Adaptation of New and Better Pediatric Drugs)
The adult Göttingen Minipig is an acknowledged model for safety assessment of antisense oligonucleotide (ASO) drugs developed for adult indications. To assess whether the juvenile Göttingen Minipig is also a suitable nonclinical model for pediatric safety assessment of ASOs, we performed an 8-week repeat-dose toxicity study in different age groups of minipigs ranging from 1 to 50 days of age. The animals received a weekly dose of a phosphorothioated locked-nucleic-acid-based ASO that was assessed previously for toxicity in adult minipigs. The endpoints included toxicokinetic parameters, in-life monitoring, clinical pathology, and histopathology. Additionally, the ontogeny of key nucleases involved in ASO metabolism and pharmacologic activity was investigated using quantitative polymerase chain reaction and nuclease activity assays. Similar clinical chemistry and toxicity findings were observed; however, differences in plasma and tissue exposures as well as pharmacologic activity were seen in the juvenile minipigs when compared with the adult data. The ontogeny study revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. These data indicate that the juvenile Göttingen Minipig is a promising nonclinical model for safety assessment of ASOs intended to treat disease in the human pediatric population. View Full-Text
Keywords: antisense oligonucleotide (ASO); endonuclease; exonuclease; locked nucleic acid (LNA); Göttingen Minipig; pediatric safety assessment; RNase H antisense oligonucleotide (ASO); endonuclease; exonuclease; locked nucleic acid (LNA); Göttingen Minipig; pediatric safety assessment; RNase H
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MDPI and ACS Style

Valenzuela, A.; Tardiveau, C.; Ayuso, M.; Buyssens, L.; Bars, C.; Van Ginneken, C.; Fant, P.; Leconte, I.; Braendli-Baiocco, A.; Parrott, N.; Schmitt, G.; Tessier, Y.; Barrow, P.; Van Cruchten, S. Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases. Pharmaceutics 2021, 13, 1442. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091442

AMA Style

Valenzuela A, Tardiveau C, Ayuso M, Buyssens L, Bars C, Van Ginneken C, Fant P, Leconte I, Braendli-Baiocco A, Parrott N, Schmitt G, Tessier Y, Barrow P, Van Cruchten S. Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases. Pharmaceutics. 2021; 13(9):1442. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091442

Chicago/Turabian Style

Valenzuela, Allan, Claire Tardiveau, Miriam Ayuso, Laura Buyssens, Chloe Bars, Chris Van Ginneken, Pierluigi Fant, Isabelle Leconte, Annamaria Braendli-Baiocco, Neil Parrott, Georg Schmitt, Yann Tessier, Paul Barrow, and Steven Van Cruchten. 2021. "Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases" Pharmaceutics 13, no. 9: 1442. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091442

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