New drug for Sickle Cell Disease targets Leukocytes
Leukocytes adhere to blood vessels as a mechanism to enter tissue where there is inflammation. Inadvertently, they pile up sickle cell red blood cells.
Mutations in the hemoglobin gene can render a person to a lifetime of sickle cell disease (SCD). While otherwise healthy individuals with one allele (gene copy) of the sickle hemoglobin (HbS) gene are carriers, the disease is seen in those with two HbS alleles – one inherited from each carrier parent. A single HbS allele can also cause SCD in a person who inherits other defects in the second hemoglobin allele.
HbS proteins aggregate into long polymers and distort red blood cells into sickle shape. Sickle-shaped red blood cells (sRBC) occlude the narrower blood vessels. In addition, leukocytes (white blood cells) stuck on blood vessel walls can compound the occlusion effect by catching sRBC. Occlusion events cause pain and can develop into numerous blood vessel-related life-threatening disease states.
When both parents have family histories of SCD, the fetus can be diagnosed before birth. Stem cell transplantation is being explored as a curative therapy before birth. However, the only relief available for SCD patients today is opioids that decrease the perception of pain.
There is a new drug, GMI-1070, that is being explored for SCD. GMI-1070 works by diminishing the expression of selectin proteins. Selectins are adhesion molecules on blood vessel walls that get expressed to catch bypassing leukocytes. Leukocytes stick to selectins and are pulled out of blood to enable them to sense local cues and make their way to sites of inflammation.
In a mouse model of SCD, the administration of GMI-1070 resulted in reduced adhesion of leukocytes and reduced capture of sRBC by leukocytes. Studies have found that selectins not only control leukocytes but also impart an adhesion-mediated drag on sRBC. Therefore, GMI-1070 is expected to affect sRBC directly as well as through leukocytes to reduce or remove occlusion events.
In a phase 2 clinical trial, 76 SCD patients hospitalized for blood vessel occlusion were enrolled; 43 patients received GMI-1070, and 33 received a placebo. For patients on GMI-1070, the time when half of the group reached resolution of their occlusion (median time) was 70 hours versus 133 for the placebo group.
Other data also provided clinically meaningful reductions. However, when statistical tests were performed on the data sets from the test and control groups, differences between the groups were not statistically significant for this small study. The trend was favorable nonetheless, and a larger phase 3 study has been registered at clinicaltrials.gov.
Tools to study SCD
Scientists are using leukocytes for research and are intrigued that a drug affecting their adhesion molecule might be used therapeutically in SCD . A leukopak is an enriched leukapheresis product collected from normal peripheral blood. A leukopak is composed of a variety of blood cells including monocytes, lymphocytes, platelets, plasma, and red cells. A leukopak contains a higher concentration of cells as compared to standard venipuncture collection methods or buffy coat products.
Real-time cell/cell adhesion under shear flow
Red blood cells adhesiveness might be involved in complications such as the vaso-occlusive crisis in SCD, thrombosis in polycythemia vera etc. . VenaFlux™ enables in vitro cell-based flow assays to study adhesion systems under physiological shear stress conditions, given the importance of shear stress in many steps of the adhesion cascade.
1. Telen MJ, et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood. 2015 Mar 2.
2. Colin Y, Le Van Kim C, El Nemer W. Red cell adhesion in human diseases. Curr Opin Hematol. 2014 Jul;21(4):369.