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Br J Haematol

Title:		"Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease"
Author(s):		Haroun E; Dutta D; Lim SH;
Address:		"Division of Hematology and Oncology, Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA"
Journal Title:		Br J Haematol
Year:		2023
Volume:		20230413
Issue:		1
Page Number:		184 - 194
DOI:		10.1111/bjh.18813
ISSN/ISBN:		1365-2141 (Electronic) 0007-1048 (Linking)
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 VOC-induced 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-alpha 1 and defensin-alpha 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology"
Keywords:		"Male Animals Mice *Volatile Organic Compounds *Anemia, Sickle Cell Oxygen Defensins haemoglobin allosteric modifier intestinal pathophysiology sickle cell disease voxelotor;"
Notes:		"MedlineHaroun, Elio Dutta, Dibyendu Lim, Seah H eng Research Support, Non-U.S. Gov't England 2023/04/14 Br J Haematol. 2023 Jul; 202(1):184-194. doi: 10.1111/bjh.18813. Epub 2023 Apr 13"