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Therapeutic drug repositioning using personalized proteomics of liquid biopsies
Gabriel Velez, … , Stephen H. Tsang, Vinit B. Mahajan
Gabriel Velez, … , Stephen H. Tsang, Vinit B. Mahajan
Published December 21, 2017
Citation Information: JCI Insight. 2017;2(24):e97818. https://doi.org/10.1172/jci.insight.97818.
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Clinical Medicine Ophthalmology Therapeutics

Therapeutic drug repositioning using personalized proteomics of liquid biopsies

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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.

Authors

Gabriel Velez, Alexander G. Bassuk, Diana Colgan, Stephen H. Tsang, Vinit B. Mahajan

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Figure 2

Personalized proteomes guide rational therapeutic repurposing for autoinflammatory disease.

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Personalized proteomes guide rational therapeutic repurposing for autoin...
(A) VEGF overexpression increases as neovascular inflammatory vitreoretinopathy (NIV) severity progresses, implicating anti-VEGF injectable therapeutics as potential NIV therapy. In contrast, TNF-α was never overexpressed in NIV eyes, explaining why injecting infliximab always failed. (B) Fundoscopic examination of a patient with stage III NIV with marked vitreous hemorrhage (VH) whose vision was reduced to “count fingers” (CF). This patient received an injection of bevacizumab (anti-VEGF). Fundoscopic examination, after injection of the therapeutic anti-VEGF antibody vitreous hemorrhage (arrow head) is resolved as vision improved to 20/70 (C) at 2 weeks and 20/50 (D) at 4 weeks. As the vitreous hemorrhage resolves (arrow head), the optic nerve head (open arrow) becomes visible. (E) Vitreous hemorrhage grade resolved after bevacizumab injection in 7 NIV eyes. (F) CD3-positive T cells (arrows) found in the vitreous of donor NIV eyes. Scale bar: 50 μm. (G) Pathway analysis revealed changes in cytokine expression in all stages of NIV. Graph of results shows the 10 pathways most affected. Pathways are organized by the log(P value) obtained from the right-tailed Fisher exact test. The class I PI3K and mTOR signaling pathways are known to be linked to T cell development. (H) Slit-lamp examination of a NIV patient with posterior uveitis showing vascular leakage of protein (flare; arrow head) and anterior chamber cells (inset; open arrow). (I) Postoperative, intravitreal injections of methotrexate (MTX) reduced anterior chamber cell grade, but did not reduce tissue damage and vascular leakage of protein into the vitreous.

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