Zhang Y, et al., Detrimental Effects of Adenosine Signaling in Sickle Cell Disease. Nat Med, 2010. 17(1): 79-86.
Metabolon results led to:
- A novel therapeutic target
- A novel biomarkers that also translate to humans
- Mechanistic understanding of signaling events that induce sickle cell disease
Key metabolomic observations:
- Adenosine was markedly increased in the SCD mouse and human subjects suggesting disease involvement
- Adenosine leads to the release of a specific red blood cell metabolite that lower oxygen affinity for hemoglobin, promoting sicklingand tissue damage.
Despite precise genetic understanding of sickle cell disease (SCD) and decades of study, therapies are limited. In a mouse model of SCD, metabolomicsidentified adenosine as a disease potentiatorand led to the identification of the adenosine 2B receptor (A2BR) as a novel therapeutic target. Specifically, antagonism of the A2BR attenuated SCD. Metabolomicanalysis revealed signaling events downstream of the A2BR that promote SCD (PKA, 2,3-DPG). These results are translatable since adenosine and 2,3-DPG were discovered to be increased in humans with SCD. Finally, the results have impact in current drugs targeting the inflammatory arm of SCD through agonismof a different adenosine receptor (the A2AR). Thus, given the dual nature of adenosine receptor activation in SCD, agonists to the A2AR may need to be exquisitely selective across the receptor sub-classes.