Editors' ChoiceSICKLE CELL DISEASE

WANTED: Natural-Born Sickler

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Science Translational Medicine  11 Jun 2014:
Vol. 6, Issue 240, pp. 240ec101
DOI: 10.1126/scitranslmed.3009588

Once we find the cause of a disease, we often expect to understand its mechanism in short order. Not so for sickle cell disease (SCD), the most common hereditary blood disorder. More than 50 years after Ingram first described that mutations in the gene that encodes β-globin proteins were linked to SCD, the mechanism by which mature red blood cells (RBCs) assume a sickled shape remains surprisingly unclear. These abnormally rigid RBCs cause trouble when they get trapped in small blood vessels. The only effective therapy—hydroxyurea—is a clever workaround: It increases the production of fetal RBCs, which are immune to sickling. Now, Zhang and colleagues provide an eminently druggable target by demonstrating that RBC sickling is due to an overactive enzyme that produces excessive quantities of the lipid sphingosine-1-phosphate (S1P).

Seeking an unbiased approach to identify pro-sickling compounds, the authors compared the metabolomic profiles from whole-blood samples of transgenic mice expressing wild-type or SCD human hemoglobin genes. Of the thousands of metabolites analyzed, S1P stood out because it was consistently higher in SCD samples. High S1P levels were also found in RBCs isolated from mice and patients with SCD.

The activity of SPHK1, the only enzyme that generates S1P in RBCs, was higher than normal in both mouse and human “sicklemic” RBCs, and a SPHK1 inhibitor could reduce RBC sickling in vitro. In mice with SCD, inhibition of SPHK1 using two distinct approaches helped prevent RBC sickling as well as other symptoms characteristic of the disease (hemolysis and enlarged spleen).

Altogether, these data make a strong case that S1P is a central player in the sickling process and that drugs that normalize S1P blood levels via inhibition of SPHK1 are promising new therapeutic agents for SCD. The next step will be to determine how mutations in the β-globin gene lead to aberrant S1P metabolism in RBCs.

Y. Zhang et al., Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression. J. Clin. Invest. 124, 2750–2761 (2014). [Full Text]

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