Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides

Lightfoot, Helen L.; Schneider, Anneliese; Hall, Jonathan

doi:10.1002/9781119070153.ch4

Cited by 3 publications

(7 citation statements)

References 76 publications

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“…This lower AUC 0–24h could be due to a faster renal clearance of RTR5001 in the juvenile age groups than in the adult. On the other hand, the plasma trough levels after each weekly dose remained relatively very low, which is in contrast to the behavior in older juvenile age groups where at the end of the experimental period, trough levels were slightly higher and indicative of tissue saturation, as has been described before for ASOs after repeated administration [ 16 , 21 , 50 , 101 , 104 , 105 ].…”

Section: Discussionmentioning

confidence: 55%

“…The short distribution half-life in the plasma of around 2–5 h for the various juvenile age groups complied with data on second-generation ASOs [ 91 , 92 ]. The biodistribution of ASOs from the plasma to other tissue compartments is related to plasma protein binding as well as to cell-surface proteins in the target organs [ 87 , 93 , 94 , 95 , 96 ], with plasma albumin being the main plasma protein responsible for protein binding in the blood compartment [ 87 , 97 , 98 , 99 , 100 ], preventing renal clearance [ 76 , 101 ]. In our study, plasma albumin concentrations in the juvenile age groups were in accordance with already published reference values, and they were 10 to 60% lower than in 6-month-old minipigs [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…ASO degradation differed between the two organs in juvenile minipigs; i.e., unmodified ASOs were degraded faster in the kidney, whereas the LNA gapmer was degraded faster in the liver. As ASO metabolism serves to be the critical driver for its tissue elimination [ 101 , 119 ], the different nuclease activity in both organs and juvenile age groups relative to the adult poses a concern of potential toxicity and underdosing. However, our observation regarding the nuclease gene expression and activity is not enough to explain the exposure profile seen in the different age groups of minipigs.…”

Section: Discussionmentioning

confidence: 99%

“…However, our observation regarding the nuclease gene expression and activity is not enough to explain the exposure profile seen in the different age groups of minipigs. Other factors, such as plasma and cell-surface protein binding, extracellular matrix binding, tissue saturation, and organ maturity, should be considered and further investigated [ 76 , 101 , 104 , 120 , 121 , 122 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, further investigation is needed on the ontogeny of these proteins. Moreover, other factors such as the turn-over kinetics of protein translation [ 101 , 138 , 139 ] and rate of ASO-directed RNase H activity (usually minutes to hours) [ 121 ] can have an impact on the degradation of the target RNA. As such, these factors could influence the dose to be used.…”

Section: Discussionmentioning

confidence: 99%

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

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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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.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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

Valenzuela

Tardiveau²,

Ayuso

et al. 2021

Pharmaceutics

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Synthesis and Characterization of Thiophosphoramidate Morpholino Oligonucleotides and Chimeras

2020

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This Article outlines the optimized chemical synthesis and preliminary biochemical characterization of a new oligonucleotide analogue called thiophosphoramidate morpholinos (TMOs). Their rational design hinges upon integrating two well-studied pharmacophores, namely, phosphorothioates (pS) and morpholinos, to create morpholino–pS hybrid oligonucleotides. Our simple synthesis strategy enables the easy incorporation of morpholino–pS moieties and therapeutically relevant sugar modifications in tandem to create novel oligonucleotide (ON) analogues that are hitherto unexplored in the oligotherapeutics arena. Exclusively TMO-modified ONs demonstrate high stability toward 3′-exonuclease. Hybridization studies show that TMO chimeras consisting of alternating TMO and DNA–pS subunits exhibit higher binding affinity toward complementary RNA relative to the canonical DNA/RNA duplex (∼10 °C). Oligonucleotides that consist entirely of TMO linkages also show higher RNA binding affinity but do not recruit ribonuclease H1 (RNase H1). Chimeric TMO analogues demonstrate high gene silencing efficacy, comparable to that of a chimeric 2′-OMe–pS/pO control, during in vitro bioassay screens designed to evaluate their potential as microRNA inhibitors of hsa-miR-15b-5p in HeLa cells.

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Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny

et al. 2023

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Antisense oligonucleotide (ASO) is a therapeutic modality that enables selective modulation of undruggable protein targets. However, dose- and sequence-dependent platelet count reductions have been reported in nonclinical studies and clinical trials. The adult Göttingen minipig is an acknowledged nonclinical model for ASO safety testing, and the juvenile Göttingen minipig has been recently proposed for the safety testing of pediatric medicines. This study assessed the effects of various ASO sequences and modifications on Göttingen minipig platelets using in vitro platelet activation and aggregometry assays. The underlying mechanism was investigated further to characterize this animal model for ASO safety testing. In addition, the protein abundance of glycoprotein VI (GPVI) and platelet factor 4 (PF4) was investigated in the adult and juvenile minipigs. Our data on direct platelet activation and aggregation by ASOs in adult minipigs are remarkably comparable to human data. Additionally, PS ASOs bind to platelet collagen receptor GPVI and directly activate minipig platelets in vitro, mirroring the findings in human blood samples. This further corroborates the use of the Göttingen minipig for ASO safety testing. Moreover, the differential abundance of GPVI and PF4 in minipigs provides insight into the influence of ontogeny in potential ASO-induced thrombocytopenia in pediatric patients.

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Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides

Cited by 3 publications

References 76 publications

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

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

Synthesis and Characterization of Thiophosphoramidate Morpholino Oligonucleotides and Chimeras

Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny

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