Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso‐occlusive crises in patients with sickle cell disease: a phase III randomized, placebo‐controlled, double‐blind study of the gardos channel blocker senicapoc (ICA‐17043)

Ataga, Kenneth I.; Reid, Marvin; Ballas, Samir K.; Yasin, Zahida; Bigelow, Carolyn; James, Luther St; Smith, Wally R.; Galactéros, Frédéric; Kutlar, Abdullah; Hull, J. Heyward; Stocker, Jonathan W.

doi:10.1111/j.1365-2141.2010.08520.x

Cited by 186 publications

(146 citation statements)

References 16 publications

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“…Future electrophysiological studies will investigate possible alterations in KCNN4 gating or ion selectivity that associated with the novel mutation V282M. Severely affected DHSt patients with these KCNN4 mutations should be considered for treatment with the Gardos channel inhibitor, senicapoc [16].…”

Section: Discussionmentioning

confidence: 99%

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Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

et al. 2015

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Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca 21 -sensitive K 1 channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD341 cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.

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Section: Discussionmentioning

confidence: 99%

“…The Gardos channel/KCNN4 is a widely expressed Ca 21 -dependent K 1 channel of intermediate conductance that mediates the major K 1 conductance of erythrocytes [15]. Inhibition of the Gardos channel in sickle disease patients reduced RBC dehydration and hemolysis, and increased blood hemoglobin levels [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

et al. 2015

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“…Supported by beneficial outcomes following K þ channel blockade in animal models of human diseases 3,4 and clinical trials, 15 we advocate KCa3.1 channels as promising new therapeutic targets in CLL. N ¼ 4).…”

Section: Openmentioning

confidence: 99%

Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade

et al. 2014

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“…Indeed, a clinical trial with senicapoc has already been established for the treatment of disorders of secondary erythrocyte hydration, such as sickle cell disease, demonstrating increased Hb and reduced markers of hemolysis in treated patients. 82,83 …”

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confidence: 99%

New insights on hereditary erythrocyte membrane defects

et al. 2016

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© Ferrata Storti Foundationmary role in the removal of aged RBCs. In order to perform these journeys RBCs must possess and maintain a significant deformability. The main author of this property is certainly the membrane, that ensures both mechanical stability and deformability. After the first proposed model of the RBC membrane skeleton 36 years ago, 1 containing the core elements of the modern model, many additional proteins have been discovered during the intervening decades, and their structures and interactions have been defined. RBC membrane structure has been extensively covered by excellent reviews.2,3 Herein we summarize the main concepts. RBC membrane is composed by a fluid double layer of lipids in which approximately 20 major proteins and at least 850 minor ones are embedded. 4 The membrane is attached to an intracellular cytoskeleton by protein-protein and lipid-protein interactions that confer the erythrocyte shape, stability and deformability. The transmembrane proteins have mainly a transporter function. However, several of these also have a structural function, usually performed by an intracytoplasmic domain interacting with cytoskeletal proteins.The lipid bilayer acts as a barrier for the retention of cations and anions within the red cells, while it allows water molecules to pass through freely. Human erythrocytes have high intracellular K + and low intracellular Na + contents when compared with the corresponding ion concentrations in the plasma. The maintenance of this cation gradient between the cell and its environment involves a passive outward movement of K + , which is pumped back by the action of an ATP-dependent Na + /K + pump in exchange for Na+ ions. This protein belongs to a class of transmembrane proteins with a transport function (Figure 1). The third and more important component of the RBC membrane is the cytoskeleton, a protein network that laminates the inner surface of the membrane. Spectrin aand β-chains, proteins 4.1, or 4.1R, and actin are the main components of this skeleton, maintaining the biconcave shape of the RBC. These components are connected to each other in two protein complexes; ankyrin and protein 4.1 complex. The former is composed by band 3 tetramers, Rh, RhAG, CD47, glycophorin A and protein 4.2. Whereas the protein 4.1 complex is composed by band 3 dimers binding adducins a-and β-, glycophorin C, GLUT1 and stomatin (Figure 1). The ends of spectrin tetramers converge toward a protein 4.1 complex (junctional complex). Electron microscopy (EM) shows that this latter links the tail of six spectrin tetramers, forming a pseudo-hexagonal arrangement. 5Spectrin tetramers include anion transporters (band 3 or chloride/bicarbonate exchange). The capability of these transporters to form aggregates could define the half-life of RBCs, causing antibody binding and removal by the spleen. Defects that interrupt this vertical structure (spectrin-actin interaction) underlie the biochemical and molecular basis of hereditary spherocytosis (HS), whereas defects in horizo...

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Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso‐occlusive crises in patients with sickle cell disease: a phase III randomized, placebo‐controlled, double‐blind study of the gardos channel blocker senicapoc (ICA‐17043)

Cited by 186 publications

References 16 publications

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade

New insights on hereditary erythrocyte membrane defects

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