Posted by (The very first report on the beneficial consequence of cyclodextrin-assisted cholesterol removal from red blood cell membranes.)
Sickle cell anemia (SCA) is a genetic hemoglobinopathy caused by a single mutation in the β-globin gene leading to the production of a structurally abnormal hemoglobin (Hb), called HbS. When deoxygenated, HbS polymerizes, which may cause sickling, which is a mechanical distortion of red blood cells (RBCs). Sickled RBCs are poorly deformable, more fragile and prone to cell lysis. (1)
Shape of normal (left) and sickle cell red blood cells (right)
source: Wikipedia https://www.bing.com/images/search?view=detailV2&ccid=Vci%2fCNKH&id
Patients with sickle cell anemia suffer from chronic pain and hemolytic anemia and repeated vaso-occlusive like events, because of the difficulty of rigid red blood cells to pass through the microcirculation. The accumulation of free Hemoglobin into the plasma as a result of hemolysis is at the origin of a pro-oxidative and inflammatory state, which participate to the development of vascular dysfunction and contribute to acute and chronic vascular complications and severe pain (2).
Current treatment options of sickle cell anemia:
For more than two decades, hydroxyurea was the only FDA-approved drug for the treatment. Since 2017, three new drugs have been approved by the FDA: voxelotor, crizanlizumab, and L-glutamine. These new therapeutic treatments along with the only really curative therapy currently available, hematopoietic stem cell transplantation from bone marrow. Significant advancements in gene therapy have recently shown promising results, but so far not approved drug is available. (3)
What can cyclodextrins do in sickle cell anemia?
Of course, again, affecting cell membrane CHOLESTEROL level!
In sickle cell anemia red blood cells display elevated membrane cholesterol levels compared to healthy controls.
In a recent study researchers from Swiss Hartis Pharma, and from University Hospital of Lyon, France demonstrated that the cholesterol-depleting 2-hydroxypropyl-beta-cyclodextrin (HPBCD), effectively reduced membrane cholesterol in sickle cell erythrocytes, in vitro.
This cyclodextrin-assisted action was found to improve deformability of red blood cells under hypoxic conditions, and to delay sickling and to reduce hemolysis.
Forty sickle cell anemia patients and ten healthy individuals were included in the different experiments of the study. Sickle cell anemia red blood cells were incubated with HPBCD (at 3 mM, for 1h, at 37°C) and the following parameters were assessed:
- RBC and supernatant cholesterol content
- RBC deformability by oxygen-gradient ektacytometry
- hemolysis by measuring free hemoglobin concentration
This study supported previous knowledge and showed that sickle cell anemia patients have higher RBC membrane cholesterol levels than healthy individuals and that this excess of cholesterol may contribute to RBC rheological changes.
Removal of cholesterol with HPBCD was found to reduce red blood cells fragility, increased their deformability and reduced red blood cells tendency to sickle under deoxygenation.
Although the presence of an abnormal lipid profile in sickle cell anemia patients has been reported several times, however, its origin and its contribution to the pathophysiology of the disease remained poorly understood.
Further research focusing on this specific lipid profile as a potential modulator of the clinical severity and as a possible therapeutic target in sickle cell anemia is, therefore, needed.
References:
1. P. Connes, Y. Lamarre, X. Waltz, S.K. Ballas, N. Lemonne, M. Etienne-Julan, et al.Haemolysis and abnormal haemorheology in sickle cell anaemia, Br. J. Haematol., 165 (4) (2014), 564-572. DOI: 10.1111/bjh.12786
2. G.J. Kato, M.T. Gladwin, M.H. Steinberg Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev., 21 (1) (2007), 37-47. DOI: 10.1016/j.blre.2006.07.001
3. Fahd A Kuriri: Hope on the Horizon: New and Future Therapies for Sickle Cell Disease. J Clin Med . 2023 Sep 1;12(17):5692. doi: 10.3390/jcm12175692
4. C. Bordat et al. Impact of elevated red blood cell membrane cholesterol in sickle cell anemia patients: Effects of BRN-002, a 2-hydroxypropyl-β-cyclodextrin derivate, on red blood cell lipids, deformability, sickling and hemolysis ,Blood Cells, Molecules, and Diseases, Volumes 113–114, 2025, 102939. DOI: 10.1016/j.bcmd.2025.102939