A Novel Strategy to Develop Therapeutic Approaches to Prevent Proliferative Vitreoretinopathy

Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
American Journal Of Pathology (Impact Factor: 4.59). 12/2011; 179(6):2931-40. DOI: 10.1016/j.ajpath.2011.08.043
Source: PubMed


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 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.

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    • "Proliferative vitreoretinopathy (PVR) is a complication of a retinal detachment and occurs in approximately 8–10% of patients developing retinal detachment [1] [2] [3]. In retinal detachment, a full-thickness retinal break exposes cells, allowing macrophages, retinal pigment epithelial cells, glial cells, and fibroblasts to migrate into the vitreous, a rich source of growth factors and cytokines correlated to PVR activity [4] [5] [6]. All these cells proliferate in the vitreous, survive, form extracellular matrix proteins, and assemble into membranes. "
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    ABSTRACT: . Proliferative vitreoretinopathy (PVR) is a severe inflammatory complication of retinal detachment. Pathological epiretinal membranes grow on the retina surface leading to contraction, and surgery fails in 5% to 10% of the cases. We evaluated the expression of VEGF-A, Otx1, Otx2, Otx3, and p53 family members from PVR specimens to correlate their role in inducing or preventing the pathology. Methods . Twelve retinal samples were taken from patients affected by PVR during therapeutic retinectomies in vitreoretinal surgery. Gene expression was evaluated using quantitative real-time reverse transcriptase PCR analysis and immunohistochemistry, using four healthy human retinae as control. Result . Controls showed basal expression of all genes. PVR samples showed little or no expression of Otx1 and variable expression of VEGF-A, Otx2, Otx3, p53, and p63 genes. Significant correlation was found among VEGF-A, Otx2, p53, and p63 and between Otx1 and Otx3. Conclusions . Otx homeobox, p53 family, and VEGF-A genes are expressed in PVR human retina. We individuated two possible pathways (VEGF-A, Otx2, p53, p63 and Otx1 and Otx3) involved in PVR progression that could influence in different manners the course of the pathology. Individuating the genetic pathways of PVR represents a novel approach to PVR therapies.
    Mediators of Inflammation 10/2013; 2013(2):857380. DOI:10.1155/2013/857380 · 3.24 Impact Factor
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    • "A recent study showed that a cocktail of neutralizing reagents targeted to multiple growth factors and cytokines was able to reduce PVR development. Antibodies against PDGF, EGF, FGF-2, IFN-γ, IL-8, TGF-α, VEGF, TGF-β, HGF, and IGF-1 to IGF-12 were effective in preventing RD in a rabbit model [129]. "
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    ABSTRACT: Eye injury is a significant disabling worldwide health problem. Proliferative Vitreoretinopathy (PVR) is a common complication that develops in up to 40-60% of patients with an open-globe injury. Our knowledge about the pathogenesis of PVR has improved in the last decades. It seems that the introduction of immune cells into the vitreous, like in penetrating ocular trauma, triggers the production of growth factors and cytokines that come in contact with intra-retinal cells, like Müller cells and RPE cells. Growth factors and cytokines drive the cellular responses leading to PVR's development. Knowledge of the pathobiological and pathophysiological mechanisms involved in posttraumatic PVR is increasing the possibilities of management, and it is hoped that in the future our treatment strategies will evolve, in particular adopting a multidrug approach, and become even more effective in vision recovery. This paper reviews the current literature and clinical trial data on the pathogenesis of PVR and its correlation with ocular trauma and describes the biochemical/molecular events that will be fundamental for the development of novel treatment strategies. This literature review included PubMed articles published from 1979 through 2013. Only studies written in English were included.
    Mediators of Inflammation 09/2013; 2013(2):269787. DOI:10.1155/2013/269787 · 3.24 Impact Factor
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    • "One in vitro study assessed for the minimum possible neutralizing set of antibodies that could be delivered to prevent cellular contraction in the presence of pathologic PVR vitreous. The minimum neutralizing set blocking PVR-related signaling was found to be a cocktail of antibodies that neutralized PDGFs, TGFα, EGF, HGF, FGF-2, TGFβ, IL-8, and IGF-1 [63]. The rationale for neutralizing PDGFs, despite evidence suggesting that the direct pathway of PDGFRα activation plays only a minor role in PVR, was to preempt against the possibility that inhibiting the indirect pathway would then potentiate and increase the bioactivity of the direct pathway. "
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    ABSTRACT: Proliferative vitreoretinopathy (PVR) is a vision-threatening disease and a common complication of surgery to correct rhegmatogenous retinal detachment (RRD). Several models of the pathogenesis of this disease have been described with some of these models focusing on the role of inflammatory cells and other models focusing on the role of growth factors and cytokines in the vitreous which come into contact with intraretinal and retinal pigment epithelial cells. New experiments have shed light on the pathogenesis of PVR and offer promising avenues for clinical intervention before PVR develops. One such target is the indirect pathway of activation of platelet-derived growth factor receptor alpha (PDGRα), which plays an important role in PVR. Clinical trials assessing the efficacy of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH), daunorubicin, and 13-cis-retinoic acid, among other therapies, have yielded mixed results. Here we review inflammatory and other mechanisms involved in the pathogenesis of PVR, we highlight important clinical trials, and we discuss how findings at the bench have the potential to be translated to the bedside.
    Mediators of Inflammation 09/2012; 2012(5):815937. DOI:10.1155/2012/815937 · 3.24 Impact Factor
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