Antisense oligonucleotides and nucleic acids generate hypersensitive platelets
Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO...
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| Veröffentlicht in: | Thrombosis research 2021-04, Vol.200, p.64-71 |
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| creator | Zaslavsky, Alexander Adams, Mackenzie Cao, Xiu Yamaguchi, Adriana Henderson, James Busch-Østergren, Peter Udager, Aaron Pitchiaya, Sethuramasundaram Tourdot, Benjamin Kasputis, Tadas Church, Samuel J. Lee, Samantha K. Ohl, Sydney Patel, Shivam Morgan, Todd M. Alva, Ajjai Wakefield, Thomas W. Reichert, Zachery Holinstat, Michael Palapattu, Ganesh S. |
| description | Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia.
Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.
Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p |
| doi_str_mv | 10.1016/j.thromres.2021.01.006 |
| format | Article |
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Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.
Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo.
Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.</description><identifier>ISSN: 0049-3848</identifier><identifier>EISSN: 1879-2472</identifier><identifier>DOI: 10.1016/j.thromres.2021.01.006</identifier><identifier>PMID: 33540294</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Antisense oligonucleotides ; Platelets ; Prostate Cancer ; Toll-like receptors</subject><ispartof>Thrombosis research, 2021-04, Vol.200, p.64-71</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-81775afeb81cb35ab458edfe407273b0cd90eca5956a3f06a74c9c65fdbef1e93</citedby><cites>FETCH-LOGICAL-c471t-81775afeb81cb35ab458edfe407273b0cd90eca5956a3f06a74c9c65fdbef1e93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.thromres.2021.01.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33540294$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zaslavsky, Alexander</creatorcontrib><creatorcontrib>Adams, Mackenzie</creatorcontrib><creatorcontrib>Cao, Xiu</creatorcontrib><creatorcontrib>Yamaguchi, Adriana</creatorcontrib><creatorcontrib>Henderson, James</creatorcontrib><creatorcontrib>Busch-Østergren, Peter</creatorcontrib><creatorcontrib>Udager, Aaron</creatorcontrib><creatorcontrib>Pitchiaya, Sethuramasundaram</creatorcontrib><creatorcontrib>Tourdot, Benjamin</creatorcontrib><creatorcontrib>Kasputis, Tadas</creatorcontrib><creatorcontrib>Church, Samuel J.</creatorcontrib><creatorcontrib>Lee, Samantha K.</creatorcontrib><creatorcontrib>Ohl, Sydney</creatorcontrib><creatorcontrib>Patel, Shivam</creatorcontrib><creatorcontrib>Morgan, Todd M.</creatorcontrib><creatorcontrib>Alva, Ajjai</creatorcontrib><creatorcontrib>Wakefield, Thomas W.</creatorcontrib><creatorcontrib>Reichert, Zachery</creatorcontrib><creatorcontrib>Holinstat, Michael</creatorcontrib><creatorcontrib>Palapattu, Ganesh S.</creatorcontrib><title>Antisense oligonucleotides and nucleic acids generate hypersensitive platelets</title><title>Thrombosis research</title><addtitle>Thromb Res</addtitle><description>Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia.
Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.
Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo.
Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.</description><subject>Antisense oligonucleotides</subject><subject>Platelets</subject><subject>Prostate Cancer</subject><subject>Toll-like receptors</subject><issn>0049-3848</issn><issn>1879-2472</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNqFUU1PGzEQtSpQSWn_Atojl03HXn_sXhAIQVsJlQucLa89mzja2MF2IvHv2RBA9FRppNHMvPdmNI-QMwpzClT-XM3LMsV1wjxnwOgcpgD5hcxoq7qaccWOyAyAd3XT8vaEfMt5BUAV7cRXctI0ggPr-Iz8vQrFZwwZqzj6RQxbO2Is3mGuTHDVa-1tZax3uVpgwGQKVsvnDaY9zRe_w2ozTs0RS_5OjgczZvzxlk_J4-3Nw_Xv-u7-15_rq7vackVL3VKlhBmwb6ntG2F6Llp0A3JQTDU9WNcBWiM6IU0zgDSK285KMbgeB4pdc0ouDrqbbb9GZzGUZEa9SX5t0rOOxut_J8Ev9SLudMsk5xImgfM3gRSftpiLXvtscRxNwLjNmvFWUcE4yAkqD1CbYs4Jh481FPTeDL3S72bovRkapnglnn0-8oP2_v0JcHkA4PSqnceks_UYLDqf0Bbtov_fjhfr5qLM</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Zaslavsky, Alexander</creator><creator>Adams, Mackenzie</creator><creator>Cao, Xiu</creator><creator>Yamaguchi, Adriana</creator><creator>Henderson, James</creator><creator>Busch-Østergren, Peter</creator><creator>Udager, Aaron</creator><creator>Pitchiaya, Sethuramasundaram</creator><creator>Tourdot, Benjamin</creator><creator>Kasputis, Tadas</creator><creator>Church, Samuel J.</creator><creator>Lee, Samantha K.</creator><creator>Ohl, Sydney</creator><creator>Patel, Shivam</creator><creator>Morgan, Todd M.</creator><creator>Alva, Ajjai</creator><creator>Wakefield, Thomas W.</creator><creator>Reichert, Zachery</creator><creator>Holinstat, Michael</creator><creator>Palapattu, Ganesh S.</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210401</creationdate><title>Antisense oligonucleotides and nucleic acids generate hypersensitive platelets</title><author>Zaslavsky, Alexander ; 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Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia.
Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.
Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo.
Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>33540294</pmid><doi>10.1016/j.thromres.2021.01.006</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Thrombosis research, 2021-04, Vol.200, p.64-71 |
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| source | Elsevier ScienceDirect Journals |
| subjects | Antisense oligonucleotides Platelets Prostate Cancer Toll-like receptors |
| title | Antisense oligonucleotides and nucleic acids generate hypersensitive platelets |
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