Investigation of the mechanism of cholesterol conjugated antisense oligonucleotide induced thrombocytopenia
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- HARADA Kosuke
- Drug Safety Research & Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
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- FURUKAWA Hideki
- Neuroscience Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
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- KOHARA Hiroshi
- Drug Safety Research & Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
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- NISHIMURA Koki
- Pharmaceutical Sciences Analytical Development, Takeda Pharmaceutical Company Limited
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- ARAI Yuta
- Pharmaceutical Sciences Analytical Development, Takeda Pharmaceutical Company Limited
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- YAMAMOTO Yuuhei
- Pharmaceutical Sciences Analytical Development, Takeda Pharmaceutical Company Limited
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- IMANISHI Akio
- Drug Safety Research & Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
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- OKAI Yoshiko
- Drug Safety Research & Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
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- SHINOZAWA Tadahiro
- Drug Safety Research & Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited
Bibliographic Information
- Other Title
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- コレステロールを付加したアンチセンスオリゴヌクレオチドによる血小板減少症のメカニズム検討
Abstract
<p>In the present study, we investigated the mechanism of antisense oligonucleotides (ASOs)-induced thrombocytopenia by in vitro and ex vivo approach. It was reported that cholesterol conjugated oligonucleotides induced platelet (PLT) count decrease in mice after an intravenous administration (Wada et al., 2016 and Nagata et al., 2021). First, we examined the platelet activation by cholesterol conjugated ASO (Chol-ASO) on flow cytometry using mouse platelet rich plasma (PRP). As a result, no PLT activation was observed with a naked ASO. On the other hand, the P-selectin positive population, which indicated activating PLT, increased along with gaining particle size in a Chol-ASO treatment. In smears of mixed PRP and Chol-ASO, aggregates with many PLTs were noted. In mice plasma, aggregates was observed after mixing plasma and Chol-ASO at concentrations ≥ 30 microM as well, suggesting that the aggregates were composed of plasma components (PC). Next, we checked the effects of sequence and modification on PC aggregation by using ASOs with four different sequences, resulting that aggregation was observed in all sequences, while modification-dependent changes were observed. Additionally, we showed that long-chain fatty acid conjugated ASO also mediates PC aggregation. Importantly, chain length and molecular shape of ligand affected the formation of aggregates.</p><p>Taken together, we demonstrated the partial mechanisms of ASO-induced thrombocytopenia that Chol-ASO forms aggregates with PC and PLTs attached to the aggregates with activation, so that PLT decreased in the blood.</p>
Journal
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- Annual Meeting of the Japanese Society of Toxicology
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Annual Meeting of the Japanese Society of Toxicology 49.1 (0), P-104-, 2022
The Japanese Society of Toxicology
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Details 詳細情報について
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- CRID
- 1390293191189747328
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- Text Lang
- ja
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- Data Source
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- JaLC
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- Abstract License Flag
- Disallowed