Abstract
Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.
Highlights
Drug discovery and development follows a relatively uniform path from mechanistic hypothesis, preclinical disease models to clinical validation
We inquire in a non-hypothesis-based manner using disease–disease networks based on common genetic origins, common protein interactions between disease genes, shared disease symptoms and disease
We find that 24 h after onset of transient middle cerebral artery occlusion (tMCAO), soluble guanylate cyclase (sGC) alpha but not beta protein levels were significantly reduced in homogenates of stroked vs. non-stroked mouse brains (Fig. 2b). sGC is broadly distributed in different brain structures such us telencephalon, thalamus, hypothalamus being expressed mainly in neurons, glial and endothelial cells of the brain microvasculature.[19,20]
Summary
Drug discovery and development follows a relatively uniform path from mechanistic hypothesis, preclinical disease models to clinical validation. Using a data-driven approach, disease–disease networks (diseosome) have been constructed in which diseases are linked based on common molecular or regulatory mechanisms,[2] such as shared genetic associations,[2] protein interactions[3,4] or gene–disease interactions.[5] These diseasomes exhibit local clusters of diseases whose molecular relationships are well understood, and unexpected clusters of surprisingly heterogeneous diseases.[3] Such clustering of disease phenotypes is likely due to underlying hidden common pathomechanisms These common mechanism clusters may provide previously unrecognized molecular definitions of these phenotypes and at the same time targets for mechanism-based drug discovery and repurposing. Disease phenotypes within this cluster, we determined the interactome-based proximity[14] of the proteins within the sGC
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