GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice
Open accessAbstract
Leukocyte adhesion in the microvasculature influences blood rheology and plays a key role in vaso-occlusive manifestations of sickle cell disease. Notably, polymorphonuclear neutrophils (PMNs) can capture circulating sickle red blood cells (sRBCs) in inflamed venules, leading to critical reduction in blood flow and vaso-occlusion. Recent studies have suggested that E-selectin expression by endothelial cells plays a key role by sending activating signals that lead to the activation of Mac-1 at the leading edge of PMNs, thereby allowing RBC capture. Thus, the inhibition of E-selectin may represent a valuable target in this disease. Here, we have tested the biologic properties of a novel synthetic pan-selectin inhibitor, GMI-1070, with in vitro assays and in a humanized model of sickle cell vaso-occlusion analyzed by intravital microscopy. We have found that GMI-1070 predominantly inhibited E-selectin–mediated adhesion and dramatically inhibited sRBC-leukocyte interactions, leading to improved microcirculatory blood flow and improved survival. These results suggest that GMI-1070 may represent a valuable novel therapeutic intervention for acute sickle cell crises that should be further evaluated in a clinical trial.
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Selectins interact with sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other interactions, ultimately contributing to vascular occlusion and sickle cell crisis.
“selectins interact with sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other interactions (924 -927) ultimately contributing to vascular occlusion and ' sickle cell crisis ' (928).”
From Biological roles of glycans (2017) · cites this paper as [928]
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“One particularly promising therapeutic outcome is based on the finding that selectins interact with sickled red cells and leukocytes in the circulation to facilitate endothelial adhesion and other interactions (924–927) ultimately contributing to vascular occlusion and “sickle cell crisis” (928).”
BackgroundPathophysiology of Sickle Cell Disease
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Self-citation
- Authors
- Chang, J., Patton, J. T., Sarkar, A., Ernst, B., Magnani, J. L., & Frenette, P. S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- GlycoMimetics (United States) (US)
- University of Basel (CH)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-09-09
- Volume
- 116
- Issue
- 10
- Pages
- 1779-1786
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2947397
- OpenAlex
- W2169864898
- Cited by
- 238
- References
- 34
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 13 · 2023: 9 · 2022: 7 · 2021: 16 · 2020: 16 · 2019: 23 · 2018: 19 · 2017: 15 · 2016: 22 · 2015: 22 · 2014: 22 · 2013: 12 · 2012: 10
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01 HL69438, T32-HL07824, T32HL007824, R01HL069438)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- E-selectin, sickle cell disease, vascular occlusion, leukocyte adhesion, sickle red blood cells, neutrophils, Mac-1, endothelial cells, microvascular blood flow, vaso-occlusive crisis, humanized mice, intravital microscopy
- MeSH terms
- Acute Disease, Anemia, Sickle Cell, Animals, Blood Flow Velocity, Cell Adhesion, Cell Line, Erythrocytes, Female, Glycolipids, Hemodynamics, Humans, Leukocytes, Male, Mice, Inbred C57BL, Vascular Diseases, P-Selectin, E-Selectin, L-Selectin, Selectins, Leukocyte Rolling, Mice, Kaplan-Meier Estimate
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