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Sequence-specific 2...
Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates
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- Slingsby, Martina H.Lundberg (author)
- Boston Children's Hospital,Harvard Medical School
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- Vijey, Prakrith (author)
- Harvard Medical School
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- Tsai, I. Ting (author)
- Harvard Medical School,Boston Children's Hospital
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- Roweth, Harvey (author)
- Harvard Medical School
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- Couldwell, Genevieve (author)
- Harvard Medical School
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- Wilkie, Adrian R. (author)
- Harvard Medical School,Boston Children's Hospital
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Gaus, Hans (author)
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- Goolsby, Jazana M. (author)
- Harvard Medical School
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- Okazaki, Ross (author)
- Harvard Medical School
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- Terkovich, Brooke E. (author)
- Harvard Medical School
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- Semple, John W. (author)
- Lund University,Lunds universitet,Trombocyt immunologi,Forskargrupper vid Lunds universitet,Platelet Immunology,Lund University Research Groups,University of Toronto
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- Thon, Jonathan N. (author)
- Harvard Medical School
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Henry, Scott P. (author)
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Narayanan, Padmakumar (author)
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- Italiano, Joseph E. (author)
- Boston Children's Hospital,Harvard Medical School
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(creator_code:org_t)
- 2021-02-11
- 2022
- English 13 s.
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In: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 107:2, s. 519-531
- Related links:
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http://dx.doi.org/10... (free)
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https://haematologic...
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https://doi.org/10.3...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Slingsby, Martin ...
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Vijey, Prakrith
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Tsai, I. Ting
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Roweth, Harvey
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Couldwell, Genev ...
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Wilkie, Adrian R ...
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show more...
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Gaus, Hans
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Goolsby, Jazana ...
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Okazaki, Ross
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Terkovich, Brook ...
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Semple, John W.
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Thon, Jonathan N ...
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Henry, Scott P.
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Narayanan, Padma ...
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Italiano, Joseph ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Haematologica
- By the university
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Lund University