Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny
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 no...
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MDPI AG,
2023-03-01T00:00:00Z.
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| LEADER | 00000 am a22000003u 4500 | ||
|---|---|---|---|
| 001 | doaj_a581d311f8d044f28e5dbaac0a1dd2a6 | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Allan Valenzuela |e author |
| 700 | 1 | 0 | |a Miriam Ayuso |e author |
| 700 | 1 | 0 | |a Laura Buyssens |e author |
| 700 | 1 | 0 | |a Chloé Bars |e author |
| 700 | 1 | 0 | |a Chris Van Ginneken |e author |
| 700 | 1 | 0 | |a Yann Tessier |e author |
| 700 | 1 | 0 | |a Steven Van Cruchten |e author |
| 245 | 0 | 0 | |a Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny |
| 260 | |b MDPI AG, |c 2023-03-01T00:00:00Z. | ||
| 500 | |a 10.3390/pharmaceutics15041112 | ||
| 500 | |a 1999-4923 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a antisense oligonucleotide (ASO) | ||
| 690 | |a Göttingen minipig | ||
| 690 | |a glycoprotein VI (GPVI) | ||
| 690 | |a platelet factor 4 (PF4) | ||
| 690 | |a ontogeny | ||
| 690 | |a thrombocytopenia | ||
| 690 | |a Pharmacy and materia medica | ||
| 690 | |a RS1-441 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Pharmaceutics, Vol 15, Iss 4, p 1112 (2023) | |
| 787 | 0 | |n https://www.mdpi.com/1999-4923/15/4/1112 | |
| 787 | 0 | |n https://doaj.org/toc/1999-4923 | |
| 856 | 4 | 1 | |u https://doaj.org/article/a581d311f8d044f28e5dbaac0a1dd2a6 |z Connect to this object online. |