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A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

ABSTRACT: Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor ? (PDGFR?) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreous-induced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR.

SUBMITTER: Pennock S

PROVIDER: S-EPMC3260857 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

Pennock Steven S Rheaume Marc-Andre MA Mukai Shizuo S Kazlauskas Andrius A

The American journal of pathology 20111028 6

Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor α (PDGFRα) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbi ...[more]

PMID: 22035642

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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.

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A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

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A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

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