Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates
(2022) In Haematologica 107(2). p.519-531- Abstract
Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- A nd sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This article focuses on the underlying cause of the more common phenotype 1, investigating the effects of ASO on platelet production and platelet function. Five phosphorothioate ASO were studied: Three 2'MOE sequences; 487660 (no effects on platelet count), 104838 (associated with phenotype 1), and 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets).... (More)
Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- A nd sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This article focuses on the underlying cause of the more common phenotype 1, investigating the effects of ASO on platelet production and platelet function. Five phosphorothioate ASO were studied: Three 2'MOE sequences; 487660 (no effects on platelet count), 104838 (associated with phenotype 1), and 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets). Human cord bloodderived megakaryocytes were treated with these ASO to study their effects on proplatelet production. Platelet activation (determined by surface Pselectin) and platelet-leukocyte aggregates were analyzed in ASO-treated blood from healthy human volunteers. None of the ASO inhibited proplatelet production by human megakaryocytes. All the ASO were shown to bind to the platelet receptor glycoprotein VI (KD ∼0.2-1.5 mM). CpG ASO had the highest affinity to glycoprotein VI, the most potent platelet-activating effects and led to the greatest formation of platelet-leukocyte aggregates. 2'MOE ASO 487660 had no detectable platelet effects, while 2'MOE ASOs 104838 and 501861 triggered moderate platelet activation and SYKdependent formation of platelet-leukocyte aggregates. Donors with higher platelet glycoprotein VI levels had greater ASO-induced platelet activation. Sequence-dependent ASO-induced platelet activation and platelet-leukocyte aggregates may explain phenotype 1 (moderate drops in platelet count). Platelet glycoprotein VI levels could be useful as a screening tool to identify patients at higher risk of ASO-induced platelet side effects.
(Less)
- author
- organization
- publishing date
- 2022-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Haematologica
- volume
- 107
- issue
- 2
- pages
- 13 pages
- publisher
- Ferrata Storti Foundation
- external identifiers
-
- scopus:85123969013
- pmid:33567808
- ISSN
- 0390-6078
- DOI
- 10.3324/haematol.2020.260059
- language
- English
- LU publication?
- yes
- id
- 0ffc2e0b-05e7-46de-a525-f92b21b58704
- date added to LUP
- 2022-04-07 15:00:34
- date last changed
- 2024-04-26 05:09:04
@article{0ffc2e0b-05e7-46de-a525-f92b21b58704,
abstract = {{<p>Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- A nd sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. This article focuses on the underlying cause of the more common phenotype 1, investigating the effects of ASO on platelet production and platelet function. Five phosphorothioate ASO were studied: Three 2'MOE sequences; 487660 (no effects on platelet count), 104838 (associated with phenotype 1), and 501861 (effects unknown) and two CpG sequences; 120704 and ODN 2395 (known to activate platelets). Human cord bloodderived megakaryocytes were treated with these ASO to study their effects on proplatelet production. Platelet activation (determined by surface Pselectin) and platelet-leukocyte aggregates were analyzed in ASO-treated blood from healthy human volunteers. None of the ASO inhibited proplatelet production by human megakaryocytes. All the ASO were shown to bind to the platelet receptor glycoprotein VI (KD ∼0.2-1.5 mM). CpG ASO had the highest affinity to glycoprotein VI, the most potent platelet-activating effects and led to the greatest formation of platelet-leukocyte aggregates. 2'MOE ASO 487660 had no detectable platelet effects, while 2'MOE ASOs 104838 and 501861 triggered moderate platelet activation and SYKdependent formation of platelet-leukocyte aggregates. Donors with higher platelet glycoprotein VI levels had greater ASO-induced platelet activation. Sequence-dependent ASO-induced platelet activation and platelet-leukocyte aggregates may explain phenotype 1 (moderate drops in platelet count). Platelet glycoprotein VI levels could be useful as a screening tool to identify patients at higher risk of ASO-induced platelet side effects.</p>}},
author = {{Slingsby, Martina H.Lundberg and Vijey, Prakrith and Tsai, I. Ting and Roweth, Harvey and Couldwell, Genevieve and Wilkie, Adrian R. and Gaus, Hans and Goolsby, Jazana M. and Okazaki, Ross and Terkovich, Brooke E. and Semple, John W. and Thon, Jonathan N. and Henry, Scott P. and Narayanan, Padmakumar and Italiano, Joseph E.}},
issn = {{0390-6078}},
language = {{eng}},
number = {{2}},
pages = {{519--531}},
publisher = {{Ferrata Storti Foundation}},
series = {{Haematologica}},
title = {{Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates}},
url = {{http://dx.doi.org/10.3324/haematol.2020.260059}},
doi = {{10.3324/haematol.2020.260059}},
volume = {{107}},
year = {{2022}},
}