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Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

ABSTRACT: PURPOSE:To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients. DESIGN:Case-control study. METHODS:Liquid biopsies were collected from 2 groups: control subjects (n = 3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n = 7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate cohorts of control patients and those with PVR-A, PVR-B, and PVR-C (n = 10 for each group). Expression changes were evaluated by analysis of variance (significant P value < .05), hierarchical cluster algorithm, and pathway analysis, to identify candidate pathways for prospective studies. RESULTS:In PVR vitreous, 29 cytokines were upregulated compared to controls. Early PVR vitreous showed upregulation of T-cell markers, profibrotic cytokines, and cytokines downstream of mTOR activation (IL-2, IL-6, and IL-13), whereas in late PVR vitreous, cytokines driving monocyte responses and stem-cell recruitment (SDF-1) prevailed. Prospective validation confirmed the differential expression of specific cytokines from PVR-A to C. CONCLUSIONS:Early PVR is characterized by activation of T cells and mTOR signaling, whereas advanced PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times.

SUBMITTER: Roybal CN

PROVIDER: S-EPMC5805631 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

Roybal C Nathaniel CN Velez Gabriel G Toral Marcus A MA Tsang Stephen H SH Bassuk Alexander G AG Mahajan Vinit B VB

American journal of ophthalmology 20171213

<h4>Purpose</h4>To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients.<h4>Design</h4>Case-control study.<h4>Methods</h4>Liquid biopsies were collected from 2 groups: control subjects (n = 3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n = 7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate coh ...[more]

PMID: 29246578

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Project description:PurposeProliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR.MethodsWe queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists.ResultsOur query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR.ConclusionsThis bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations.Translational relevanceNovel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

Project description:PurposeThe purpose of the study was to evaluate the efficacy and safety of intravitreal pirfenidone for inhibition of proliferative vitreoretinopathy (PVR) in a model of penetrating ocular injury.Patients and methodsPenetrating trauma was induced on the retina of rabbit and treated either with 0.1 ml of phosphate-buffered saline (PBS) or 0.1 ml of 0.5% pirfenidone, and development of PVR was evaluated clinically and graded after 1 month. Histopathology and immunohistochemistry with transforming growth factor beta (TGFβ), alpha smooth muscle actin (αSMA), and collagen-1 were performed to assess the fibrotic changes. Expression of cytokines in the vitro-retinal tissues at different time points following pirfenidone and PBS injection was examined by RT-PCR. Availability of pirfenidone in the vitreous of rabbit at various time points was determined by high-performance liquid chromatography following injection of 0.1 ml of 0.5% pirfenidone. In normal rabbit eye, 0.1 ml of 0.5% pirfenidone was injected to evaluate any toxic effect.ResultsClinical assessment and grading revealed prevention of PVR formation in pirfenidone-treated animals, gross histology, and histopathology confirmed the observation. Immunohistochemistry showed prevention in the expression of collagen-I, αSMA, and TGFβ in the pirfenidone-treated eyes compared to the PBS-treated eyes. Pirfenidone inhibited increased gene expression of cytokines observed in control eyes. Pirfenidone could be detected up to 48 h in the vitreous of rabbit eye following single intravitreal injection. Pirfenidone did not show any adverse effect following intravitreal injection; eyes were devoid of any abnormal clinical sign, intraocular pressure, and electroretinography did not show any significant change and histology of retina remained unchanged.ConclusionThis animal study shows that pirfenidone might be a potential therapy for PVR. Further clinical study will be useful to evaluate the clinical application of pirfenidone.

Project description:Purpose: The development of vitreoretinal scars remains an unsolved challenge in clinical practice and often leads to repeated revision surgery and blindness due to lack of efficient therapy. The aim of this study was to characterize the cellular and molecular environment in vitreoretinal scar tissue from patients with proliferative vitreoretinopathy (PVR) in comparison to membranes of the vitreoretinal junction, in order to subsequently identify potential drug treatment options using bioinformatics techniques. Methods: A total of 23 patients undergoing vitrectomy for retinal detachment due to proliferative vitreoretinopathy (PVR, n = 15), idiopathic macular hole (MH, n = 10) or idiopathic macular pucker (MP, n = 8), were included in this study. Vitreoretinal samples were analysed by RNA sequencing, MS-CyTOF proteomic and by conventional immunohistochemistry. The cellular microenvironment was assessed by bioinformatics cell type enrichment analysis. Drug target screening was performed by using a transcriptome-based drug-repurposing approach using drug-exposure transcriptome data from public available databases. Results: RNA sequencing of vitreoretinal tissue samples showed distinct transcriptional differences of PVR, ERM and ILM samples allowing an accurate clustering according to the tissue types. The cellular microenvironment of PVR membranes was characterized by the enrichment of melanocytes, astrocytes and various immune cell types, such as M2 macrophages. Differential gene expression (DEG) analysis revealed XX up- and XX downregulated genes in PVR compared to ILM. Among them, FN1 (fibronectin1), SPARC (osteonectin) and various collagens were among the most upregulated factors in PVR, contributing to biological processes such as the organization of extracellular structures, the regulation of cell adhesion and the morphogenesis of blood vessels. Finally, we identified 13 drugs that induce a gene expression profile complementary to the PVR signature and thus represent potential therapeutic options for PVR, including aminocaproic acid and various topoisomerase 2A inhibitors such as doxorubicin, etoposide and mitoxantrone. Conclusion: The present study reveals significant differences in the transcriptional signature of vitreoretinal scar tissue including PVR, MP and ILM tissue. Among a plethora of differentially expressed genes, FN1 and SPARC appeared to be central mediators underlying PVR development. Based on the transcriptome analyses, aminocaproic acid and topoisomerase-2 inhibitors, such as doxorubicin, etoposide and mitoxantrone, were identified as compatible drugs for the treatment of PVR.

Project description: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-? 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.

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Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

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Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

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