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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Development of antithrombotic miniribozymes that target peripheral tryptophan hydroxylase.

Serotonin is not only a neurotransmitter in the central nervous system, but also a ubiquitous hormone in the periphery involved in vasoconstriction and platelet function. Tryptophan hydroxylase is the rate-limiting enzyme in serotonin biosynthesis. By gene targeting, we have shown that serotonin is synthesized independently by two different tryptophan hydroxylase isoenzymes in peripheral tissues and neurons and identified a neuronal tryptophan hydroxylase isoform. Mice deficient in peripheral tryptophan hydroxylase ( TPH1) and serotonin exhibit a reduced risk of thrombosis and thromboembolism. Therefore, we designed several antitph1 hammerhead miniribozymes and tested their cleavage activity against short synthetic Tph1 RNA substrates. In vitro cleavage studies demonstrated site-specific cleavage of Tph1 mRNA that was dependent on substrate/miniribozyme ratio and duration of exposure to miniribozyme. Interestingly, we detected different in vitro cleavage rates after we had cloned the miniribozymes into tRNA expression constructs, and found one with a high cleavage rate. We also demonstrated that this active tRNA-miniribozyme chimera is capable of selectively cleaving native Tph1 mRNA in vivo, with concomitant downregulation of the serotonin biosynthesis. Therefore, this Tph1-specific miniribozyme may provide a novel and effective form of gene therapy that may be applicable to a variety of thrombotic diseases.[1]

References

  1. Development of antithrombotic miniribozymes that target peripheral tryptophan hydroxylase. Peter, J.U., Alenina, N., Bader, M., Walther, D.J. Mol. Cell. Biochem. (2007) [Pubmed]
 
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