Biochemists Reduce Sickling and Progression of Sickle Cell Disease in Mice

Newswise — New preclinical research on the molecular mechanisms responsible for sickle cell disease could aid efforts to develop much needed treatments for this devastating blood disorder that affects millions worldwide.

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An international research team led by biochemists at The University of Texas Health Science Center at Houston (UTHealth) reduced the sickling of red blood cells in a mouse model of the disease. Results of the study appear today in The Journal of Clinical Investigation.

The scientists did this by manipulating a small molecule known as sphingosine-1-phosphate (S1P), which they report is found in elevated levels in people with sickle cell disease.

“Our research could lead to therapeutic opportunities,” said Yang Xia, M.D., Ph.D., the study’s senior author and a professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School. “We validated our findings in isolated blood cells from patients with sickle cell disease.”

The sickling of red blood cells is the hallmark of this disease. Normally shaped like a donut, the diseased cells instead have a crescent-like appearance. This can lead to anemia, chest pain, lung problems and stroke. Xia’s lab screened approximately 7,000 metabolites for functional differences between sickle cell disease mice and controls. They found that sickle cell disease significantly increases S1P and that S1P is generated by sphingosine kinase 1 (SphK1).

They are directly proportional, meaning the more SphK1, the more S1P, and vice versa, Xia said.

When SphK1 was inhibited in a mouse model of sickle cell disease, red blood cells lived longer and had less sickling. When the scientists treated blood samples taken from sickle cell disease patients with SphK1 inhibitors, the investigators found a significant reduction in the number of sickle cells.

Extending the cells’ life span is particularly important because diseased cells only last from 10 to 20 days compared to about 120 days for healthy cells in humans. Reducing the sickling is also significant because sickled cells are more prone to being damaged when passing through narrow capillaries. This can cause anemia and other dangerous complications.

“This work could lead to novel treatments for sickle cell disease,” said Harinder Juneja, M.D., study co-author and director of hematology at the UTHealth Medical School and Memorial Hermann-Texas Medical Center.

“The study has identified a lipid bioactive molecule involved in sickling and disease progression. The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target,” Juneja said.

Rod Kellems, Ph.D., study co-author and chairman of the Department of Biochemistry and Molecular Biology at the UTHealth Medical School, added, “This research provides insight into how red blood cells work, revealing that SphK1-mediated elevation of S1P contributes to sickling and promotes disease progression and highlights potential therapeutic opportunities for sickle cell disease.”

Other UTHealth co-authors include Yujin Zhang, Ph.D., Ah-Lim Tsai, Ph.D., Modupe Idowu, M.D., Jianping Jin, Ph.D., Anren Song, Ph.D., Kaiqi Sun, Wenzheng Zhang, Ph.D., Vladimir Berka, Ph.D., Chonghua Li, Mikhail Bogdanov, Ph.D, Wei Wang, M.D., Ph.D., and William Dowhan, Ph.D. Dowhan 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.

Xia, Kellems, Jin, Bogdanov, Wenzheng Zhang and Dowhan are on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston.

The study titled “Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression” received support from National Institutes of Health grants (HL119549, P01HL114457, DK077748, HL11354, DK083559, HL095820), the American Heart Association (10GRNT3760081 and 12IRG9150001 and China Scholarship Council (2009637520).