Assessing a Novel Depot Delivery Strategy for Noninvasive Administration of VEGF/PDGF RTK Inhibitors for Ocular Neovascular Disease

Robbie, Scott; Leithner, Peter Lundh von; Ju, Meihua; Lange, Clemens; King, Andrew G.; Adamson, Peter; Lee, Dennis; Sychterz, Caroline; Coffey, Peter; Ng, Y. Jack; Bainbridge, James; Shima, David T.

doi:10.1167/iovs.12-10169

Cited by 52 publications

(61 citation statements)

References 44 publications

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“…Additional agents of interest (59) include angiopoietin-2, a Tie2 receptor agonist, expressed at the inner retinal surface where pathological vascular tufts are forming in ROP mice (60). Also a possibility is pazopanib, an FDA-approved oral therapeutic for advanced renal cell carcinoma that inhibits several VEGFRs, with in vivo tests focused mainly on VEGFR-2 although pazopanib also inhibits two Platelet-derived Growth Factors and KIT thus reducing angiogenesis; the related but somewhat more soluble GW771806 can be administered in eye drops (61). We have previously described that retinal vessels formed by angiogenesis in the ROP mouse model also express on their vascular cells α v β 3 and α v β 5 integrins, aminopeptidase A, and aminopeptidase N receptors that can selectively bind to circulating bacteriophage-carried peptide ligands including a proapoptotic peptide that kills vascular cells (62).…”

Section: Discussionmentioning

confidence: 99%

The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

Sidman

Lawrence³

et al. 2015

Sci. Transl. Med.

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Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, named vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. Here, we have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys), abbreviated as D(CLPRC), and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors, VEGFR-1 and Neuropilin-1 (NRP-1). Delivery of Vasotide in eye drops or via intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of retinopathy of prematurity (ROP) markedly decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less invasive applications to combat pathological angiogenesis in retinal disorders.

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Section: Discussionmentioning

confidence: 99%

The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

Sidman

Lawrence³

et al. 2015

Sci. Transl. Med.

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“…Aganirsen, an anti-angiogenic aptamer inhibits laser induced CNV almost completely in African green monkeys at 86 µg when applied twice daily for 2 days prior to laser and continued with same regimen for an additional 14 days [41]. In some studies, Pazopanib, a tyrosine kinase inhibitor has been shown to inhibit laser induced CNV in rats but in some other studies no efficacy of Pazopanib has been found [44], [45], [46]. A pazopanib analog, GW771806 is currently undergoing clinical trials [46].…”

Section: Discussionmentioning

confidence: 99%

“…In some studies, Pazopanib, a tyrosine kinase inhibitor has been shown to inhibit laser induced CNV in rats but in some other studies no efficacy of Pazopanib has been found [44], [45], [46]. A pazopanib analog, GW771806 is currently undergoing clinical trials [46]. We envisage that PPADS may offer some unique advantages over other molecules, specifically when considering the systems being targeted, i.e.…”

Section: Discussionmentioning

confidence: 99%

Topical Application of PPADS Inhibits Complement Activation and Choroidal Neovascularization in a Model of Age-Related Macular Degeneration

et al. 2013

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Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly. AMD patients have elevated levels of membrane attack complex (MAC) in their choroidal blood vessels and retinal pigment epithelium (RPE). MAC forms pores in cell membranes. Low levels of MAC result in an elevation of cytokine release such as vascular endothelial growth factor (VEGF) that promotes the formation of choroidal neovascularization (CNV). High levels of MAC result in cell lysis and RPE degeneration is a hallmark of advanced AMD. The current standard of care for CNV associated with wet AMD is intravitreal injection of anti-VEGF molecules every 4 to 12 weeks. Such injections have significant side effects. Recently, it has been found that membrane pore-forming proteins such as α-haemolysin can mediate their toxic effects through auto- and paracrine signaling and that complement-induced lysis is amplified through ATP release followed by P2X receptor activation. We hypothesized that attenuation of P2X receptor activation may lead to a reduction in MAC deposition and consequent formation of CNV. Hence, in this study we investigated topical application of the purinergic P2X antagonist Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) as a potential treatment for AMD. We found that 4.17 µM PPADS inhibited formation of HUVEC master junctions and master segments by 74.7%. In a human complement mediated cell lysis assay, 104 µM PPADS enabled almost complete protection of Hepa1c1c7 cells from 1% normal human serum mediated cell lysis. Daily topical application of 4.17 mM PPADS for 3 days attenuated the progression of laser induced CNV in mice by 41.8% and attenuated the deposition of MAC at the site of the laser injury by 19.7%. Our data have implications for the future treatment of AMD and potentially other ocular disorders involving CNV such as angioid streaks, choroidal rupture and high myopia.

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“…10 Lesion number and area were quantified using ImageJ (http://imagej.nih.gov/ ij/; provided in the public domain by the National Institutes of Health, Bethesda, MD, USA). Lesion area is represented in most figures as percentage of control; however, statistics were done on raw pixel measurements.…”

Section: In Vivo Imagingmentioning

confidence: 99%

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

Nagai

Leithner

Izumi-Nagai

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function.METHODS. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies.RESULTS. The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction. CONCLUSIONS.The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGF-A antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.Keywords: animal models, neovascularization, VEGF-A T he transformative nature of recent therapeutic developments for neovascular age-related macular degeneration (nAMD) has triggered an exponential increase in ophthalmic drug development efforts over the past decade. 1 The most prevalent assay used to benchmark potential new nAMD compounds and therapeutic strategies is rodent laser-induced choroidal neovascularization (lCNV). [2][3][4][5] This model is used to assess antiangiogenic activity and the ability to reduce vascular permeability, two hallmarks of nAMD. Moreover, because of the ease of imaging the posterior pole, lCNV is often used as a secondary pharmacology model during drug development for other conditions, such as cancer. However, the lCNV model has several limitations, including acute, intense laser injury to the photoreceptors, RPE, and choriocapillaris to induce angiogenesis, the accumulation of hypertrophic scar tissue, and a natural regression of the neovascularization. 6 Therefore, factors that initiate the CNV, and long-term analysis of the consequences of the neovessels to the retina, cannot be readily studied. Here we describe a novel genetic model of multifocal, bilateral spontaneous choroidal neovascularization (sCNV), which leads to early, persistent neovascular lesions that leak and lead to retinal edema, local gliosis and focal photoreceptor dysfunction, and death. Approximately 10% to 15% of the lesions will eventually anastomose with the...

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Assessing a Novel Depot Delivery Strategy for Noninvasive Administration of VEGF/PDGF RTK Inhibitors for Ocular Neovascular Disease

Cited by 52 publications

References 44 publications

The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease

Topical Application of PPADS Inhibits Complement Activation and Choroidal Neovascularization in a Model of Age-Related Macular Degeneration

Spontaneous CNV in a Novel Mutant Mouse Is Associated With Early VEGF-A–Driven Angiogenesis and Late-Stage Focal Edema, Neural Cell Loss, and Dysfunction

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