Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.

Animals Blood Platelets Humans Mice Nucleic Acids Oligonucleotides, Antisense Pharmaceutical Preparations Phosphorothioate Oligonucleotides
Antisense oligonucleotides Platelets Prostate Cancer Toll-like receptors

Journal

Thrombosis research
ISSN: 1879-2472
Titre abrégé: Thromb Res
Pays: United States
ID NLM: 0326377

Informations de publication

Date de publication:
04 2021
Historique:
received: 15 01 2020
revised: 07 12 2020
accepted: 04 01 2021
pubmed: 5 2 2021
medline: 22 6 2021
entrez: 4 2 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.thromres.2021.01.006 PMID: 33540294 PMC: PMC8264460
pubmed: 33540294
pii: S0049-3848(21)00015-3
doi: 10.1016/j.thromres.2021.01.006
pmc: PMC8264460
mid: NIHMS1711667
pii:
doi:

Substances chimiques

Nucleic Acids 0
Oligonucleotides, Antisense 0
Pharmaceutical Preparations 0
Phosphorothioate Oligonucleotides 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

64-71

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM105671
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL114405
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM131835
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Références

Nat Biotechnol. 2019 Jun;37(6):640-650
pubmed: 31036929
Toxicol Appl Pharmacol. 2004 Nov 15;201(1):66-83
pubmed: 15519609
Front Immunol. 2015 Mar 02;6:83
pubmed: 25784910
Nauchnye Doki Vyss Shkoly Biol Nauki. 1990;(2):31-5
pubmed: 1693862
Mol Ther Nucleic Acids. 2019 Mar 1;14:142-157
pubmed: 30594893
Thromb Res. 2017 Oct;158:8-15
pubmed: 28783513
PLoS One. 2017 Nov 6;12(11):e0187574
pubmed: 29107969
Ann Indian Acad Neurol. 2018 Jan-Mar;21(1):3-8
pubmed: 29720791
Nat Rev Immunol. 2011 Apr;11(4):264-74
pubmed: 21436837
J Clin Invest. 1998 Feb 1;101(3):667-76
pubmed: 9449701
Toxicol Sci. 2018 Aug 1;164(2):613-626
pubmed: 29846725
Nat Rev Drug Discov. 2020 Oct;19(10):673-694
pubmed: 32782413
Shock. 2015 Sep;44(3):265-71
pubmed: 25944792
J Immunol. 1979 Dec;123(6):2479-83
pubmed: 501081
Blood. 2014 Jul 31;124(5):791-802
pubmed: 24755410
Cell Immunol. 2011;271(2):401-12
pubmed: 21889130
Circ Res. 2013 Jan 4;112(1):103-12
pubmed: 23071157
Proc Natl Acad Sci U S A. 1978 Jan;75(1):280-4
pubmed: 75545
Drug Discov Today. 2017 May;22(5):823-833
pubmed: 28159625
J Vasc Surg. 2016 Nov;64(5):1450-1458.e1
pubmed: 26482993
Thromb Haemost. 1978 Aug 31;40(1):175-95
pubmed: 103239
Neuron. 2017 Jun 21;94(6):1056-1070
pubmed: 28641106
Expert Opin Investig Drugs. 2008 Dec;17(12):1955-62
pubmed: 19012510
J Cell Biol. 2012 Aug 20;198(4):561-74
pubmed: 22908309
Biochim Biophys Acta. 1999 Dec 10;1489(1):69-84
pubmed: 10806998
Circulation. 2000 Oct 17;102(16):1931-6
pubmed: 11034941
Mol Ther. 2017 May 3;25(5):1069-1075
pubmed: 28366767
Front Biosci (Landmark Ed). 2017 Jun 1;22:1867-1883
pubmed: 28410150
J Exp Med. 2015 Feb 9;212(2):129-37
pubmed: 25646267
Nucleic Acid Ther. 2017 Jun;27(3):121-129
pubmed: 28145801

Auteurs

Alexander Zaslavsky (A)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: azaslavs@med.umich.edu.

Mackenzie Adams (M)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Xiu Cao (X)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Adriana Yamaguchi (A)

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

James Henderson (J)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Peter Busch-Østergren (P)

Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark.

Aaron Udager (A)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Sethuramasundaram Pitchiaya (S)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

Benjamin Tourdot (B)

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.

Tadas Kasputis (T)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Samuel J Church (SJ)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Samantha K Lee (SK)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Sydney Ohl (S)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Shivam Patel (S)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Todd M Morgan (TM)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Ajjai Alva (A)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.

Thomas W Wakefield (TW)

Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan Medical School, Ann Arbor, MI, USA.

Zachery Reichert (Z)

Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.

Michael Holinstat (M)

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

Ganesh S Palapattu (GS)

Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address: gpalapat@med.umich.edu.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Sang › Cellules sanguines › Plaquettes › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Sondes moléculaires › Sondes d'acide nucléique › Éléments antisens (génétique) › Oligonucléotides antisens › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Préparations pharmaceutiques › Antisense oligonucleotides and nucleic acids...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Polynucléotides › Oligonucléotides › Oligonucléotides phosphorothioates › Antisense oligonucleotides and nucleic acids...