Journal article
Therapeutic drug repositioning using personalized proteomics of liquid biopsies
JCI insight, Vol.2(24), e97818
12/21/2017
DOI: 10.1172/jci.insight.97818
PMCID: PMC5752263
PMID: 29263305
Abstract
BACKGROUND.
In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing — time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes.
METHODS.
Vitreous biopsies from NIV patients were profiled by an antibody array for expression of 200 cytokine-signaling proteins. Non-NIV controls were compared with NIV samples from various stages of disease progression. Patterns were identified by 1-way ANOVA, hierarchical clustering, and pathway analysis. Subjects treated with repositioned therapies were followed longitudinally.
RESULTS.
Proteomic profiles revealed molecular pathways in NIV pathologies and implicated superior and inferior targets for therapy. Anti-VEGF injections resolved vitreous hemorrhages without the need for vitrectomy surgery. Methotrexate injections reversed inflammatory cell reactions without the side effects of corticosteroids. Anti–IL-6 therapy prevented recurrent fibrosis and retinal detachment where all prior antiinflammatory interventions had failed. The cytokine array also showed that TNF-
α
levels were normal and that corticosteroid-sensitive pathways were absent in fibrotic NIV, helping explain prior failure of these conventional therapeutic approaches.
CONCLUSIONS.
Personalized proteomics can uncover highly personalized therapies for autoinflammatory disease that can be timed with specific pathologic activities. This precision medicine strategy can also help prevent delivery of ineffective drugs. Importantly, proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment using available drugs.
Proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment of inflammatory diseases using available drugs.
Details
- Title: Subtitle
- Therapeutic drug repositioning using personalized proteomics of liquid biopsies
- Creators
- Gabriel Velez - Omics Laboratory, Stanford University, Palo Alto, California, USAAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, Iowa, USADiana Colgan - Omics Laboratory, Stanford University, Palo Alto, California, USAStephen H Tsang - Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, andVinit B Mahajan - Omics Laboratory, Stanford University, Palo Alto, California, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(24), e97818
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.97818
- PMID
- 29263305
- PMCID
- PMC5752263
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- R01EY026682; R01EY024665; R01EY025225; R01EY024698; R21AG050437; P30EY026877 / National Institutes of Health T32GM007337 / ; 2013103 / ; 5P30EY019007; R01EY018213; R01EY024698; R21AG050437 / ; 5P30CA013696 / ; N/A / ;
- Language
- English
- Date published
- 12/21/2017
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984071727502771
Metrics
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