Treating sickle cell disease by targeting HbS polymerization
Open accessAbstract
Although the root cause of sickle cell disease is the polymerization of hemoglobin S (HbS) to form fibers that make red cells less flexible, most drugs currently being assessed in clinical trials are targeting the downstream sequelae of this primary event. Less attention has been devoted to investigation of the multiple ways in which fiber formation can be inhibited. In this article, we describe the molecular rationale for 5 distinct approaches to inhibiting polymerization and also discuss progress with the few antipolymerization drugs currently in clinical trials.
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The most efficient means of treating sickle cell disease is interrupting disease pathophysiology by preventing deoxyHbS polymerization.
“The most efficient means of treatment is interrupting disease pathophysiology by preventing deoxyHbS polymerization.”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [5]
The Introduction (page unavailable) identifies HbS polymerization as the root cause of sickle cell pathology and argues for directing more research and trials toward inhibiting it. It does not establish that preventing polymerization is the most efficient treatment; the Conclusion (page unavailable) says polymerization inhibitors still face hurdles before clinical use. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPreventing deoxyHbS polymerization can be accomplished by inducing sufficiently high levels of HbF in most sickle erythrocytes.
“This can be accomplished by inducing sufficiently high levels of HbF in most sickle erythrocytes.5”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [5]
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Experiments on Hemoglobin in Single Crystals and Silica Gels Distinguish among Allosteric Models
Henry, E. R., Mozzarelli, A., Viappiani, C., Abbruzzetti, S., Bettati, S., Ronda, L., Bruno, S., & Eaton, W. A. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.04.037 · Cited by 37 · see citing works
Self-citationOptimizing hydroxyurea therapy for sickle cell anemia
Ware, R. E. (2015) · Hematology · doi:10.1182/asheducation.v2015.1.436.3917688 · Cited by 37 · see citing works
New insights into sickle cell disease
Kato, G. J. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000241 · Cited by 36 · see citing works
Allogeneic stem cell transplantation for sickle cell disease
Robinson, T. M., & Fuchs, E. J. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000282 · Cited by 35 · see citing works
A procedure for decreasing the level of 2,3-bisphosphoglycerate in red cells invitro
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The trials and hopes for drug development in sickle cell disease
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Lehrer‐Graiwer, J., Howard, J., Hemmaway, C. J., Awogbade, M., Telfer, P. T., Layton, M., Mant, T., Dufu, K., Hutchaleelaha, A., Koller, T. D., et al. (2015) · Blood · doi:10.1182/blood.v126.23.542.542 · Cited by 29 · see citing works
Universality of supersaturation in protein-fiber formation
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The Effect of 2,3-DPG on the Sickling Phenomenon
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Genome editing of HBG1 and HBG2 to induce fetal hemoglobin
Métais, J.-Y., Doerfler, P. A., Mayuranathan, T., Bauer, D. E., Fowler, S. C., Hsieh, M. M., Katta, V., Keriwala, S., Lazzarotto, C. R., Luk, K., et al. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000820 · Cited by 177 · see citing works
Fetal hemoglobin in sickle cell anemia
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Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies
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Self-citationEmbryonic and fetal human hemoglobins: structures, oxygen binding, and physiological roles
Manning, J. M., Manning, L. R., Dumoulin, A., Padovan, J. C., & Chait, B. (2020) · Subcellular Biochemistry · doi:10.1007/978-3-030-41769-7_11 · Cited by 30 · see citing works
- Authors
- Eaton, W. A., & Bunn, H. F.
- Affiliations
- National Institutes of Health (US)
- Brigham and Women's Hospital (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2017-05-18
- Volume
- 129
- Issue
- 20
- Pages
- 2719-2726
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC5437829
- OpenAlex
- W2605267194
- Semantic Scholar
- 50a6ac0b94b7d5f22e58824afd641d836ec9d269
- Cited by
- 255
- References
- 111
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 38 · 2023: 26 · 2022: 35 · 2021: 25 · 2020: 32 · 2019: 27 · 2018: 25 · 2017: 8
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- sickle cell disease, hemoglobin S, polymerization inhibition, erythrocyte deformability, clinical trials
- MeSH terms
- Anemia, Sickle Cell, Animals, Clinical Trials as Topic, Fetal Hemoglobin, Hemoglobin, Sickle, Humans, Oxygen, Polymerization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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