A novel composition of endogenous metabolic modulators improves red blood cell properties in sickle cell disease.

Autor: van Dijk MJ; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands.; Center for Benign Hematology, Thrombosis and Hemostasis-Van Creveldkliniek University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Traets MJM; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., van Oirschot BA; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Ruiter TJJ; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands.; Section Metabolic Diagnostics, Department of Genetics University Medical Center Utrecht Utrecht University Utrecht The Netherlands., de Wilde JRA; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Bos J; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., van Solinge WW; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Koziel MJ; Axcella Therapeutics Cambridge Massachusetts USA., Jans JJM; Section Metabolic Diagnostics, Department of Genetics University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Wani R; Axcella Therapeutics Cambridge Massachusetts USA.; Boehringer Ingelheim Pharmaceuticals, Inc. Cambridge Massachusetts USA., van Beers EJ; Center for Benign Hematology, Thrombosis and Hemostasis-Van Creveldkliniek University Medical Center Utrecht Utrecht University Utrecht The Netherlands., van Wijk R; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands., Rab MAE; Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht Utrecht University Utrecht The Netherlands.; Department of Hematology University Medical Center Utrecht Utrecht The Netherlands.
Jazyk: angličtina
Zdroj: EJHaem [EJHaem] 2024 Feb 02; Vol. 5 (1), pp. 21-32. Date of Electronic Publication: 2024 Feb 02 (Print Publication: 2024).
DOI: 10.1002/jha2.850
Abstrakt: The most common forms of sickle cell disease (SCD) are sickle cell anemia (SCA; HbSS) and HbSC disease. In both, especially the more dense, dehydrated and adherent red blood cells (RBCs) with reduced deformability are prone to hemolysis and sickling, and thereby vaso-occlusion. Based on plasma amino acid profiling in SCD, a composition of 10 amino acids and derivatives (RCitNacQCarLKHVS; Axcella Therapeutics, USA), referred to as endogenous metabolic modulators (EMMs), was designed to target RBC metabolism. The effects of ex vivo treatment with the EMM composition on different RBC properties were studied in SCD ( n  = 9 SCA, n  = 5 HbSC disease). Dose-dependent improvements were observed in RBC hydration assessed by hemocytometry (MCV, MCHC, dense RBCs) and osmotic gradient ektacytometry (Ohyper). Median (interquartile range [IQR]) increase in Ohyper compared to vehicle was 4.9% (4.0%-5.5%), 7.5% (6.9%-9.4%), and 12.8% (11.5%-14.0%) with increasing 20×, 40×, and 80X concentrations, respectively (all p  < 0.0001). RBC deformability (EImax using oxygen gradient ektacytometry) increased by 8.1% (2.2%-12.1%; p  = 0.0012), 9.6% (2.9%-15.1%; p  = 0.0013), and 13.3% (5.7%-25.5%; p  = 0.0007), respectively. Besides, RBC adhesion to subendothelial laminin decreased by 43% (6%-68%; p  = 0.4324), 58% (48%-72%; p  = 0.0185), and 71% (49%-82%; p  = 0.0016), respectively. Together, these results provide a rationale for further studies with the EMM composition targeting multiple RBC properties in SCD.
Competing Interests: R.v.W. and M.R. received research funding from Axcella Therapeutics and Pfizer. E.v.B. and R.v.W. are consultants for Pfizer. E.v.B., R.v.W., and M.R. receive research funding and are consultants for Agios Pharmaceuticals Inc. M.J.K. and R.W. are employees of Axcella Therapeutics. The remaining authors declare no competing financial interests.
(© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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