Abstract
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.
Highlights
The expression and activity of nucleases involved in antisense oligonucleotide (ASO) metabolism and pharmacologic activity were assessed in the blood, kidney, and liver of juvenile Göttingen Minipigs
A similar toxicity profile was noted in juvenile minipigs as previously reported in adult minipigs following repeated ASO administration
Lower plasma and tissue exposure to RTR5001 were noted in younger minipigs up to weaning than in older or adult minipigs
Summary
Antisense oligonucleotides (ASOs) belong to a therapeutic modality designed to treat specific diseases by selectively modulating the gene expression of disease-associated proteins. 12–24 nucleotides in length, ASOs are designed to hybridize with a specific and complementary mRNA, resulting in inhibition of protein translation [1]. More than a dozen RNA-targeting therapeutics are authorized for use, while many others are in development for various indications for which no or limited treatment options are available [2,3,4]. One mechanism by which ASOs inhibit RNA translation is through RNA degradation by the RNase H-dependent cleavage mechanism [5,6].
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