Predictive value of VEGF A and VEGFR2 polymorphisms in the response to intravitreal ranibizumab treatment for wet AMD

Cruz-González, Fernando; Cabrillo-Estévez, L.; López-Valverde, Gloria; Cieza-Borrella, Clara; Hernández-Galilea, Emiliano; González-Sarmiento, Rogelio

doi:10.1007/s00417-014-2585-7

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…As Rap1b is implicated in promoting VEGF/VEGFR2-mediated angiogenesis, 15,16 which is important in neovascular AMD, 18,19 we restricted activation of Rap1 to only the Rap1a isoform by using Rap1b -/- mice. We previously published that activation of Rap1a with the chemical, 8-CPT-2Me-cAMP, delivered as an intravitreal injection, reduced CNV in Rap1b -/- mice.…”

Section: Resultsmentioning

confidence: 99%

“…18,19 Since the fold decrease in CNV volume in scAAV2-CARap1a versus scAAV2-Con was comparable to that from intravitreal anti-VEGF versus IgG, we wished to determine if activation of Rap1a affected VEGF expression or signaling. We previously found that laser-induced CNV increased NADPH oxidase-generated ROS in CNV 20 and VEGF protein in RPE/choroidal lysates in wild-type C57Bl/6 mice.…”

Section: Resultsmentioning

confidence: 99%

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Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization

Wang

Han

Bretz

et al. 2016

Molecular Therapy - Methods & Clinical Development

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To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV), self-complementary adeno-associated virus 2 (scAAV2) with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con) or constitutively active Rap1a (scAAV2-CARap1a) showed strong GFP at the 5 × 108 viral particle/µl dose 5 weeks later without altering retinal morphology or function. Compared to scAAV2-Con- or phosphate-buffered saline (PBS)-injected, eyes injected with scAAV2-CARap1a had increased Rap1 in retinal pigment epithelial (RPE)/choroidal lysates and a significant reduction in CNV volume 7 days after laser, comparable to eyes that received intravitreal anti-VEGF versus IgG control. scAAV2-CARap1a-, but not anti-VEGF-, injected eyes had increased pan-cadherin in RPE/choroids. In cultured RPE cells, increased active Rap1a inhibited TNFα-induced disassociation of junctional pan-cadherin/β-catenin complexes, increased transepithelial electrical resistance through an interaction of β-catenin with phosphorylated scaffold protein, IQGAP1, and inhibited choroidal endothelial cell (CEC) transmigration of an RPE monolayer. This evidence shows that increased Rap1a activity specifically in RPE cells is sufficient to reduce CEC transmigration and CNV and involves IQGAP1-mediated protection of RPE junctional complexes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization

Wang

Han

Bretz

et al. 2016

Molecular Therapy - Methods & Clinical Development

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“…This SNP was reported in three studies. 12 13 21 Although a significant association was reported only in one study, 16 for the recessive model, the effect of the genotype CC pointed to the same direction in studies of Cruz-Gonzalez et al 20 and Park et al 12 (OR=1.619 16 and OR=3.442, 12 with VA being the criterion), which strongly predicted a pooled OR=2.362 for the total analysis and the result was statistically significant (p=0.001), indicating that anti-VEGF treatment was more effective in patients with AMD having the rs833061 CC genotype. This relationship was strengthened further and became highly significant when a sub-analysis was conducted including studies with a VA-positive outcome criterion or the treatment of RBZ only, with OR=3.226 or OR=3.091, respectively.…”

Section: Discussionmentioning

confidence: 99%

Association between VEGF-A and VEGFR-2 polymorphisms and response to treatment of neovascular AMD with anti-VEGF agents: a meta-analysis

Xiong

et al. 2016

Br J Ophthalmol

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AimsThe purpose of this study is to investigate whether gene polymorphisms of the vascular endothelial growth factor A (VEGF-A) and its receptor (VEGFR-2) have a pharmacogenetics effect on the anti-VEGF treatment for neovascular age-related macular degeneration (nAMD).MethodsWe carried out a meta-analysis focusing on the relationship between VEGF-related gene polymorphisms and treatment response of nAMD.ResultsFor the single nucleotide polymorphisms (SNPs) within VEGF-A and VEGFR-2, anti-VEGF treatment was much more effective in patients with nAMD having rs833061 (CC vs TT:OR=2.222, 95% CI 1.252 to 3.944, p=0.006; CT vs TT: OR=2.537,95% CI 1.478 to 4.356, p=0.001 and CC vs CT+TT: OR=2.362, 95% CI 1.414 to 3.946, p=0.001), particularly for Asians (CC vs TT: OR=2.903, 95% CI 1.150 to 7.330, p=0.024; CT vs TT: OR=3.849, 95% CI 1.522 to 9.733, p=0.004 and CC vs CT+TT: OR=3.339, 95% CI 1.369 to 8.145, p=0.008, respectively). In subgroup analysis, rs833061 was more likely to be a predictor of response to anti-VEGF therapy specifically when ranibizumab (RBZ) only regime was adopted or visual acuity (VA) was taken as the standardised assessment of outcome. No association with response to anti-VEGF treatment was detected for the other eight polymorphisms.ConclusionsPharmacogenetics of VEGF-A polymorphism rs833061 may play a positive role in response to anti-VEGF therapy for nAMD.

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“…The results of each patient’s HER2, Erb2, and BRCA testing determine the chemotherapeutic regimens and surgical approaches. Single nucleotide polymorphisms (SNPs) from several genes—CFH, C2, C3, AMRS, HTRA1, hepatic lipase, VEGF, and VEGFR—are suspected to play a role in the development of advanced AMD but clinical studies cannot consistently predict patients’ responses to therapy based on genetic abnormalities [82,83,84,85]. Nonetheless, genetic studies continue with the hope that individualized therapy can someday be tailored to the presence or absence of AMD susceptibility genes.…”

Section: Present Datamentioning

confidence: 99%

Individualized Treatment of Neovascular Age-Related Macular Degeneration: What are Patients Gaining? Or Losing?

Stewart

2015

JCM

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The widespread use of drugs that bind diffusible vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (AMD). The pivotal ranibizumab and aflibercept registration trials featured monthly intravitreal injections for 12 months, during which visual acuities and macular edema rapidly improved for the first 3 months and modest gains or stabilization continued until the primary endpoint. In many subsequent trials, patients were evaluated monthly and treated as-needed (PRN) according to the results of visual acuity (VA) testing, fundus examinations and optical coherence tomography scans. Compared to monthly-treated control groups, PRN treated patients require fewer injections during the first year but they also experience smaller VA gains (1–3 letters). A small number of prospective trials that directly compared monthly with PRN therapy showed that VA gains with discontinuous therapy lag slightly behind those achieved with monthly injections. Physicians recognize that monthly office visits with frequent intraocular injections challenge patients’ compliance, accrue high drug and professional service costs, and clog office schedules with frequently returning patients. To decrease the numbers of both office visits and anti-VEGF injections without sacrificing VA gains, physicians have embraced the treat-and-extend strategy. Treat-and-extend has not been studied as rigorously as PRN but it has become popular among both vitreoretinal specialists and patients. Despite the possible risks associated with discontinuous therapy (decreased VA and increased macular fluid), most physicians individualize treatment (PRN or treat-and-extend) for the majority of their patients. This review chapter explores the many advantages of individualized therapy, while balancing these against suboptimal responses due to the decreased frequency of anti-VEGF injections.

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Predictive value of VEGF A and VEGFR2 polymorphisms in the response to intravitreal ranibizumab treatment for wet AMD

Abstract: Polymorphisms of VEGF A seem to influence the different response to antiangiogenic treatment in patients with AMD in our population, although further investigation is needed to know the mechanisms of this relationship.

Cited by 24 publications

References 28 publications

Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization

Retinal pigment epithelial cell expression of active Rap 1a by scAAV2 inhibits choroidal neovascularization

Association between VEGF-A and VEGFR-2 polymorphisms and response to treatment of neovascular AMD with anti-VEGF agents: a meta-analysis

Individualized Treatment of Neovascular Age-Related Macular Degeneration: What are Patients Gaining? Or Losing?

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