Gabriel Velez1,2,3, Alexander G Bassuk4, Diana Colgan1,2, Stephen H Tsang5,6, Vinit B Mahajan1,2,7. 1. Omics Laboratory, Stanford University, Palo Alto, California, USA. 2. Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA. 3. Medical Scientist Training Program, and. 4. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA. 5. Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, and. 6. Department of Pathology & Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York, USA. 7. Palo Alto Veterans Administration, Palo Alto, California, USA.
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.
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.
Entities:
Keywords:
Drug therapy; Ophthalmology; Proteomics; Retinopathy; Therapeutics
Authors: Vinit B Mahajan; Kori A Elkins; Stephen R Russell; H Culver Boldt; Karen M Gehrs; Thomas A Weingeist; Edwin M Stone; Michael D Abràmoff; Dawei Liu; James C Folk Journal: Retina Date: 2011-01 Impact factor: 4.256
Authors: Vinit B Mahajan; John G Vallone; Jonathan H Lin; Robert F Mullins; Audrey C Ko; James C Folk; Edwin M Stone Journal: Mol Vis Date: 2010-06-08 Impact factor: 2.367
Authors: Gabriel Velez; C Nathaniel Roybal; Diana Colgan; Stephen H Tsang; Alexander G Bassuk; Vinit B Mahajan Journal: JAMA Ophthalmol Date: 2016-04 Impact factor: 7.389
Authors: Katherine J Wert; Susanne F Koch; Gabriel Velez; Chun-Wei Hsu; MaryAnn Mahajan; Alexander G Bassuk; Stephen H Tsang; Vinit B Mahajan Journal: Hum Mutat Date: 2019-08-26 Impact factor: 4.878
Authors: Maria L Lozano; Cristina Segú-Vergés; Mireia Coma; María T Álvarez-Roman; José R González-Porras; Laura Gutiérrez; David Valcárcel; Nora Butta Journal: Int J Mol Sci Date: 2021-06-27 Impact factor: 5.923
Authors: Gabriel Velez; Daniel A Machlab; Peter H Tang; Yang Sun; Stephen H Tsang; Alexander G Bassuk; Vinit B Mahajan Journal: PLoS One Date: 2018-02-21 Impact factor: 3.240
Authors: Gabriel Velez; Peter H Tang; Thiago Cabral; Galaxy Y Cho; Daniel A Machlab; Stephen H Tsang; Alexander G Bassuk; Vinit B Mahajan Journal: Transl Vis Sci Technol Date: 2018-09-26 Impact factor: 3.283
Authors: Gabriel Velez; Jing Yang; Angela S Li; Stephen H Tsang; Alexander G Bassuk; Vinit B Mahajan Journal: Sci Rep Date: 2019-05-20 Impact factor: 4.379
Authors: Peter H Tang; Teja Chemudupati; Katherine J Wert; James C Folk; MaryAnn Mahajan; Stephen H Tsang; Alexander G Bassuk; Vinit B Mahajan Journal: Am J Ophthalmol Case Rep Date: 2020-02-24
Authors: Timothy M Boyce; S Scott Whitmore; Katayoun Varzavand; Stephen R Russell; Elliott H Sohn; James C Folk; Edwin M Stone; Ian C Han Journal: Am J Ophthalmol Date: 2021-07-21 Impact factor: 5.488
Authors: Gabriel Velez; Young Joo Sun; Saif Khan; Jing Yang; Jonathan Herrmann; Teja Chemudupati; Robert E MacLaren; Lokesh Gakhar; Soichi Wakatsuki; Alexander G Bassuk; Vinit B Mahajan Journal: Cell Rep Date: 2020-01-21 Impact factor: 9.423