Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

JCI Insight 2019 Jun 6;4(11). Epub 2019 Jun 6.

Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.127652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629138PMC
June 2019
7 Reads

Publication Analysis

Top Keywords

fbn1mgr/mgr mice
12
drug repurposing
8
subcellular pathways
8
transcriptomic data
8
mice
5
predicted subcellular
4
taa determinants
4
mice predicted
4
wild-type mice
4
associated drug-treated
4
drug-treated mfs
4
pathways associated
4
muscle contractility
4
contractility key
4
mfs wild-type
4
reduced muscle
4
associated reduced
4
mice fbn1mgr/mgr
4
key taa
4
patients mfs
4

Similar Publications