Biochemists at the University of Texas Health Science Center at Houston are leading a new research effort exploring the molecular mechanisms responsible for sickle cell disease (SCD), in hopes of developing treatments for the genetic disorder, which is associated with high morbidity and mortality.
The researchers’ new study, recently published in the Journal of Clinical Investigation, found that sphingosine-1-phosphate (S1P), a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces, is highly elevated in the blood of mice and humans with SCD. Having found this, they manipulated S1P and successfully reduced the sickling of red blood cells in a mouse model of the disease.
Dr. Yang Xia, the study’s senior author and a professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School, explained in a press release from UTHSC that the team validated their findings in isolated blood cells from patients with sickle cell disease.
SCD results from the initiation of sickling of red blood cells, the fundamental process of disease pathogenesis, which causes a crescent-like appearance of the typically donut-shaped cells. Ultimately, SCD can lead to anemia, chest pain, lung problems, and stroke.
The team conducted nonbiased metabolomic screening, using liquid and gas chromatography coupled with mass spectral analysis to measure and compare metabolite profiles in the whole blood of controls. They screened 7,000 metabolites, detecting 251 metabolites in the circulation of both WT and SCD Tg mice and concluding that sphingosine kinase 1 (SphK1) and S1P are directly proportional: the more SphK1, the more S1P.
By reducing the sickling, researchers extended the cell’s life span, which is particularly important, considering that diseased cells only last from 10 to 20 days, versus about 120 days for healthy cells.
With this study, Xia’s lab expects to find new treatments for SCD, as they provided evidence that PF-543, a newly developed potent SPHK1 inhibitor, is an effective treatment to decrease sickling, reticulocyte count, hemolysis, and inflammation.
“The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target,” said Harinder Juneja, study co-author and director of hematology at the UTHealth Medical School and Memorial Hermann-Texas Medical Center.
Despite being the most prevalent autosomal recessive disorder, affecting millions worldwide, there is currently only one FDA-approved drug — hydroxyurea — for treating SCD, which helps to decrease the number of pain crises and episodes of acute chest syndrome.
UTHealth co-authors on this study include Yujin Zhang, Ah-Lim Tsai, Modupe Idowu, Jianping Jin, Anren Song, Kaiqi Sun, Wenzheng Zhang, Vladimir Berka, Chonghua Li, Mikhail Bogdanov, Wei Wang, and William Dowhan (who is the John S. Dunn Chair in Biochemistry & Molecular Biology at the UTHealth Medical School).
Additional co-authors include of Chen Ning, M.D., Ph.D., and Weiru Zhang, M.D., Ph.D., the First Xiangya Hospital, Central South University, Changsha, Hunan, China; Qibo Zhang, Ph.D., Michael Milburn and Danny Alexander, Ph.D., Metabolon Inc., Durham, N.C; Mostafa Ahmed and Martin Safo, Virginia Commonwealth University, Richmond, Va.; Han Lin, Jun Zhang, M.D., and Pumin Zhang, Ph.D., Baylor College of Medicine; Osheiza Abdulmalik, Ph.D., Children’s Hospital of Philadelphia; and Gregory Kato, M.D., National Heart, Lung, and Blood Institute.
The study received support from National Institutes of Health grants, the American Heart Association and China Scholarship Council.