Improvement of hemolytic anemia with GBT1118 is renoprotective in transgenic sickle mice

Ren, Guohui; Setty, Suman; Zhang, Xu; Susma, Alexandru; Ruiz, Maria Armila; Minshall, Richard D.; Lash, James P.; Saraf, Santosh L.

doi:10.1182/bloodadvances.2022007809

Cited by 4 publications

(5 citation statements)

References 27 publications

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“…Townes SCD mice were randomly divided into two groups: Group 1 mice received only GBT1118 chow and Group 2 mice only control chow 21 for a total of 7 weeks. GBT1118 chow and control chow were provided by Global Blood Therapeutics.…”

Section: Methodsmentioning

confidence: 99%

“…21 In these mice, renal protection genes were upregulated in the glomerular and tubular cells, with the consequence of reducing albuminuria and proteinuria. 21 We previously found in experiments using female transgenic Townes SCD mice that they exhibited the intestinal pathophysiologic abnormalities 8,9 similar to that in patients with SCD. Compared with controls consisting of non-sickle cell mice, they showed disrupted intestinal barrier functions and increased intestinal microbial load, especially after the induction of experimental VOC by water deprivation.…”

Section: Effects Of Gbt1118 a Voxelotor Analog On Intestinal Pathophy...mentioning

confidence: 99%

“…19,20 It also protects SCD mice from renal damage due to chronic haemolysis and haemoglobinuria by reducing the urine reactive oxygen species. 21 In these mice, renal protection genes were upregulated in the glomerular and tubular cells, with the consequence of reducing albuminuria and proteinuria. 21 We previously found in experiments using female transgenic Townes SCD mice that they exhibited the intestinal pathophysiologic abnormalities 8,9 similar to that in patients with SCD.…”

Section: Effects Of Gbt1118 a Voxelotor Analog On Intestinal Pathophy...mentioning

confidence: 99%

“…GBT1118 improved oxygen delivery to hypoxic tissues in various mouse models of hypoxic tissue injury 19,20 . It also protects SCD mice from renal damage due to chronic haemolysis and haemoglobinuria by reducing the urine reactive oxygen species 21 . In these mice, renal protection genes were upregulated in the glomerular and tubular cells, with the consequence of reducing albuminuria and proteinuria 21 …”

Section: Introductionmentioning

confidence: 99%

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

2023

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Effects Of Gbt1118 a Voxelotor Analog On Intestinal Pathophy...mentioning

confidence: 99%

Section: Effects Of Gbt1118 a Voxelotor Analog On Intestinal Pathophy...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

2023

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“…Furthermore, concentrations of cell-free hemoglobin were directly associated with kidney injury molecule-1 in the urine, and the presence of hemoglobinuria was associated with a 14-fold greater risk of CKD progression on longitudinal follow-up [25, 83]. Treating transgenic SCD mice with GBT1118, a mouse analog of voxelotor that reduces sickle RBC hemolysis, from 12 to 24 weeks of age reduces hemoglobinuria and tubular hemosiderin deposition, leading to improvements in biomarkers of glomerular and tubular injury and stabilization of albuminuria, proteinuria, and serum cystatin-C concentrations [84].…”

Section: Pathophysiologymentioning

confidence: 99%

Sickle Cell Disease and CKD: An Update

Zahr,

Saraf

2023

Am J Nephrol

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Background: Sickle cell disease is an inherited red blood cell disorder that affects approximately 100,000 people in the U.S. and 25 million people worldwide. Vaso-occlusion and chronic hemolysis lead to dysfunction to vital organ systems, with the kidneys being among the most commonly affected organs. Summary: Early renal manifestations include medullary ischemia with loss of urine concentrating ability and hyperfiltration. This can be followed by progressive damage characterized by persistent albuminuria and a decline in the estimated glomerular filtration rate. The risk of sickle nephropathy is greater in those with the APOL1 G1 and G2 kidney risk variants and variants in HMOX1 and lower in those that co-inherit α-thalassemia. Therapies to treat sickle cell disease-related kidney damage focus on sickle cell disease modifying therapies (e.g. hydroxyurea) or those adopted from the non-sickle cell disease kidney literature (e.g. renin-angiotensin-aldosterone system inhibitors), although data on their clinical efficacy are limited to small studies with short follow up periods. Kidney transplantation for end-stage kidney disease improves survival compared to hemodialysis but is underutilized in this patient population. Key Messages: Kidney disease is a major contributor to early mortality and more research is needed to understand the pathophysiology and to develop targeted therapies to improve kidney health in sickle cell disease.

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Effects of GBT1118, a voxelotor analog, on bone disease in sickle cell disease mice

Xiao,

He,

Hurley

2024

Sci Rep

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Improvement of hemolytic anemia with GBT1118 is renoprotective in transgenic sickle mice

Abstract: Key Points A reduction in hemolysis with voxelotor analog, GBT1118, reduced hemoglobinuria and kidney injury biomarkers in transgenic sickle mice. Improved chronic hemolysis preserved kidney function and histopathologic and ultrastructural changes in transgenic sickle mice.

Cited by 4 publications

References 27 publications

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

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

Sickle Cell Disease and CKD: An Update

Effects of GBT1118, a voxelotor analog, on bone disease in sickle cell disease mice

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