Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration

Jaffe, Glenn J.; Ciulla, Thomas A.; Ciardella, Antonio P.; Devin, François; Dugel, Pravin U.; Eandi, Chiara M; Masonson, Harvey; Monés, Jordi; Pearlman, Joel; Maftouhi, M. Quaranta El; Ricci, Federico; Westby, Keith; Patel, Sudi

doi:10.1016/j.ophtha.2016.10.010

Cited by 117 publications

(73 citation statements)

References 40 publications

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“…In the present study, we examined a cross section of patients with wet AMD attending for anti‐VEGF treatment who have developed an element of sub‐retinal fibrosis. Debate exists around the histological nature of SHRM, which can include diverse material such as fibrin, exudation, blood, neovascular tissue, fibrosis and vitelliform material . In the present cohort, observed changes were attributed to sub‐retinal fibrosis as these were chronic nAMD cases under long‐term anti‐VEGF treatment.…”

Section: Discussionsupporting

confidence: 89%

“…Debate exists around the histological nature of SHRM, which can include diverse material such as fibrin, exudation, blood, neovascular tissue, fibrosis and vitelliform material. [7][8][9][10]12,20 In the present cohort, observed changes were attributed to sub-retinal fibrosis as these were chronic nAMD cases under long-term anti-VEGF treatment.…”

Section: Discussionmentioning

confidence: 56%

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Swept‐source optical coherence tomography angiography features of sub‐retinal fibrosis in neovascular age‐related macular degeneration

Balaskas

Ali

Saddik

et al. 2018

Clinical Exper Ophthalmology

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 56%

Swept‐source optical coherence tomography angiography features of sub‐retinal fibrosis in neovascular age‐related macular degeneration

Balaskas

Ali

Saddik

et al. 2018

Clinical Exper Ophthalmology

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“…Currently, the premier treatment available for ocular neovascular diseases is anti-VEGF-A therapy, which mainly targets vascular endothelial cells (ECs) (1). However, drug resistance to anti-VEGF-A therapy has emerged as a serious challenge (2) and effects of anti-VEGF-A therapy decline for most patients within the first 4 years of treatment (3). Moreover, not all patients with neovascular diseases are responsive to anti-VEGF-A therapy (4,5), suggesting the existence of other important angiogenic components.…”

mentioning

confidence: 99%

Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK

Jiang

Lin

Tang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti-VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.

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“…Also, the low solubility may enable a prolonged treatment effect, and such an effect may differ from biologic antibodies that target these same pathways and are currently in human clinical trials. 43 Thus, pazopanib has ideal physical properties conducive to studying this agent in the SCS. In fact, triamcinolone acetonide has similar physical properties and was found to be an excellent compound for effective delivery in the SCS (long-term action, low systemic levels).…”

Section: Discussionmentioning

confidence: 99%

A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs

Tran

Craven

Wabner

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model.MethodsForty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study.ResultsIn 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1–treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells.ConclusionsIntravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.

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Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration

Cited by 117 publications

References 40 publications

Swept‐source optical coherence tomography angiography features of sub‐retinal fibrosis in neovascular age‐related macular degeneration

Swept‐source optical coherence tomography angiography features of sub‐retinal fibrosis in neovascular age‐related macular degeneration

Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK

A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs

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