Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease

Abstract

Voxelotor is an allosteric haemoglobin (Hb) modulator that binds covalently and reversibly to Hb alpha chain to facilitate improved Hb-O 2 affinity and arterial oxygen. It, therefore, reduces the susceptibility of erythrocytes carrying Haemoglobin S to sickle. In this study, we have used GBT1118, an analog of voxelotor, to treat male Townes sickle cell disease (SCD) mice to investigate whether the Hb modulator could attenuate the intestinal pathophysiologic changes associated with SCD. Compared with mice fed with control chow, GBT1118-treated mice showed improvement in the intestinal pathophysiology. These mice exhibited improved small intestinal barrier functions, reduced intestinal microbial density, reduced enterocyte injury, lower serum lipopolysaccharides and smaller spleens. These improvements were observed after only 3 weeks of GBT1118 treatment. Benefits were also observed after experimentally-induced vaso-occlusive crisis (VOC). Recovery from the VOCinduced changes was faster in mice that were treated with GBT1118. The improved small intestinal barrier function was associated with higher expression of genes encoding enterocyte E-cadherin, JAM-A, ZO-1, MUC-2 and occludin while the lower intestinal microbial density associated with higher expression of genes encoding the antimicrobial peptides defensin-α 1 and defensin-α 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology.

Hope on the Horizon: New and Future Therapies for Sickle Cell Disease

“…Other mechanisms of action have recently been attributed to the therapeutic effect of voxelotor in SCD. A study by Tarasev et al explored the effect of GBT1118, a voxelotor analog, on hypoxia-induced lethal and sub-hemolytic RBC membrane damage [27,28]. Findings indicated that GBT1118 prevented hypoxia-induced membrane damage in sickled RBCs, indicating that voxelotor may also act through other mechanisms not related to hemoglobin-oxygen affinity.…”