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Credit: Graham Colm
Through a series of preclinical experiments, scientists discovered they could reduce the sickling of red blood cells (RBCs) and slow the progression of sickle cell disease (SCD).
In a mouse model of SCD and blood samples from SCD patients, the researchers reduced sickling by manipulating sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1).
Yang Xia, MD, PhD, of The University of Texas Health Science Center at Houston, and colleagues described this work in The Journal of Clinical Investigation.
The scientists first discovered that S1P, a lipid enriched and stored in RBCs, is elevated in mice with SCD. Further investigation revealed that elevated SPHK1 activity underlies the increased levels of S1P and contributes to RBC sickling.
To confirm SPHK1’s role in SCD, the researchers tested 2 SPHK1 inhibitors, SK1-I and PF-543, in cells from mice with SCD. Both agents successfully inhibited SPHK1 activity and reduced S1P levels in a dose-dependent manner, but PF-543 demonstrated greater potency.
In subsequent experiments, PF-543 decreased intravascular hemolysis and reduced inflammation in mice with SCD. The treatment also decreased tissue injury and splenomegaly and increased survival in the mice.
When the scientists knocked down SPHK1 in hematopoietic stem cells (HSCs), they observed decreased sickling and reticulocytes in SCD chimeras, resulting from a reduction in S1P levels.
Knocking down SPHK1 in HSCs also decreased intravascular hemolysis, prolonged RBC life span, reduced inflammation, decreased splenomegaly and tissue injury, and increased survival in the mice.
Experiments in cells from patients with SCD showed that SPHK1 activity and S1P levels were elevated and directly contributed to sickling. So the researchers decided to evaluate how PF-543 would affect these cells.
Treating cells with PF-543 significantly inhibited hypoxia-induced SPHK1 activity and prevented the elevation of S1P in a dose-dependent manner. The treatment also significantly reduced the percentage of sickled cells in a dose-dependent manner.
Finally, the scientists found that S1P-induced sickling was independent of S1P receptor activation. S1P receptor antagonists did not inhibit hypoxia-induced sickling in cells from SCD patients. And treatment with S1P did not enhance sickling under hypoxic conditions.
“This work could lead to novel treatments for sickle cell disease,” said study author Harinder Juneja, MD, of The University of Texas Health Science Center. “The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target.”
Coauthor Rod Kellems, PhD, also of The University of Texas Health Science Center, 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.” 
Credit: Graham Colm
Through a series of preclinical experiments, scientists discovered they could reduce the sickling of red blood cells (RBCs) and slow the progression of sickle cell disease (SCD).
In a mouse model of SCD and blood samples from SCD patients, the researchers reduced sickling by manipulating sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1).
Yang Xia, MD, PhD, of The University of Texas Health Science Center at Houston, and colleagues described this work in The Journal of Clinical Investigation.
The scientists first discovered that S1P, a lipid enriched and stored in RBCs, is elevated in mice with SCD. Further investigation revealed that elevated SPHK1 activity underlies the increased levels of S1P and contributes to RBC sickling.
To confirm SPHK1’s role in SCD, the researchers tested 2 SPHK1 inhibitors, SK1-I and PF-543, in cells from mice with SCD. Both agents successfully inhibited SPHK1 activity and reduced S1P levels in a dose-dependent manner, but PF-543 demonstrated greater potency.
In subsequent experiments, PF-543 decreased intravascular hemolysis and reduced inflammation in mice with SCD. The treatment also decreased tissue injury and splenomegaly and increased survival in the mice.
When the scientists knocked down SPHK1 in hematopoietic stem cells (HSCs), they observed decreased sickling and reticulocytes in SCD chimeras, resulting from a reduction in S1P levels.
Knocking down SPHK1 in HSCs also decreased intravascular hemolysis, prolonged RBC life span, reduced inflammation, decreased splenomegaly and tissue injury, and increased survival in the mice.
Experiments in cells from patients with SCD showed that SPHK1 activity and S1P levels were elevated and directly contributed to sickling. So the researchers decided to evaluate how PF-543 would affect these cells.
Treating cells with PF-543 significantly inhibited hypoxia-induced SPHK1 activity and prevented the elevation of S1P in a dose-dependent manner. The treatment also significantly reduced the percentage of sickled cells in a dose-dependent manner.
Finally, the scientists found that S1P-induced sickling was independent of S1P receptor activation. S1P receptor antagonists did not inhibit hypoxia-induced sickling in cells from SCD patients. And treatment with S1P did not enhance sickling under hypoxic conditions.
“This work could lead to novel treatments for sickle cell disease,” said study author Harinder Juneja, MD, of The University of Texas Health Science Center. “The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target.”
Coauthor Rod Kellems, PhD, also of The University of Texas Health Science Center, 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.”
Credit: Graham Colm
Through a series of preclinical experiments, scientists discovered they could reduce the sickling of red blood cells (RBCs) and slow the progression of sickle cell disease (SCD).
In a mouse model of SCD and blood samples from SCD patients, the researchers reduced sickling by manipulating sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1).
Yang Xia, MD, PhD, of The University of Texas Health Science Center at Houston, and colleagues described this work in The Journal of Clinical Investigation.
The scientists first discovered that S1P, a lipid enriched and stored in RBCs, is elevated in mice with SCD. Further investigation revealed that elevated SPHK1 activity underlies the increased levels of S1P and contributes to RBC sickling.
To confirm SPHK1’s role in SCD, the researchers tested 2 SPHK1 inhibitors, SK1-I and PF-543, in cells from mice with SCD. Both agents successfully inhibited SPHK1 activity and reduced S1P levels in a dose-dependent manner, but PF-543 demonstrated greater potency.
In subsequent experiments, PF-543 decreased intravascular hemolysis and reduced inflammation in mice with SCD. The treatment also decreased tissue injury and splenomegaly and increased survival in the mice.
When the scientists knocked down SPHK1 in hematopoietic stem cells (HSCs), they observed decreased sickling and reticulocytes in SCD chimeras, resulting from a reduction in S1P levels.
Knocking down SPHK1 in HSCs also decreased intravascular hemolysis, prolonged RBC life span, reduced inflammation, decreased splenomegaly and tissue injury, and increased survival in the mice.
Experiments in cells from patients with SCD showed that SPHK1 activity and S1P levels were elevated and directly contributed to sickling. So the researchers decided to evaluate how PF-543 would affect these cells.
Treating cells with PF-543 significantly inhibited hypoxia-induced SPHK1 activity and prevented the elevation of S1P in a dose-dependent manner. The treatment also significantly reduced the percentage of sickled cells in a dose-dependent manner.
Finally, the scientists found that S1P-induced sickling was independent of S1P receptor activation. S1P receptor antagonists did not inhibit hypoxia-induced sickling in cells from SCD patients. And treatment with S1P did not enhance sickling under hypoxic conditions.
“This work could lead to novel treatments for sickle cell disease,” said study author Harinder Juneja, MD, of The University of Texas Health Science Center. “The study provides a better understanding of the pathogenesis of the disease and reveals a new therapeutic target.”
Coauthor Rod Kellems, PhD, also of The University of Texas Health Science Center, 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.”