TY  - JOUR
A1  - Langhauser, Friederike
A1  - Casas, Ana I.
A1  - Dao, Vu-Thao-Vi
A1  - Guney, Emre
A1  - Menche, Jörg
A1  - Geuss, Eva
A1  - Kleikers, Pamela W. M.
A1  - López, Manuela G.
A1  - Barabási, Albert-L.
A1  - Kleinschnitz, Christoph
A1  - Schmidt, Harald H. H. W.
T1  - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection
JF  - npj Systems Biology and Applications
N2  - 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.
KW  - neurology
KW  - pharmacology
KW  - systems biology
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236381
VL  - 4
ER  - 
TY  - JOUR
A1  - Kleikers, Pamela W. M.
A1  - Hooijmans, Carlijn
A1  - Göb, Eva
A1  - Langhauser, Friederike
A1  - Rewell, Sarah S. J.
A1  - Radermacher, Kim
A1  - Ritskes-Hoitinga, Merel
A1  - Howells, David W.
A1  - Kleinschnitz, Christoph
A1  - Schmidt, Harald H. H. W.
T1  - A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation
JF  - Scientific Reports
N2  - Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX\(_{2}\) to be a major therapeutic target in stroke. Systematic review and MA of all available NOX\(_{2}\)\(^{-/y}\) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX\(_{2}\) as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.
KW  - focal cerebral ischemia
KW  - darbepoetin alpha
KW  - mice
KW  - translational stroke research
KW  - colony-stimulating factor
KW  - NADPH oxidase inhibitors
KW  - chronic kidney disease
KW  - diabetes mellitus
KW  - oxidative stress
KW  - search filter
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151401
VL  - 5
IS  - 13428
ER  -