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New Therapies of Neovascular AMD-Beyond Anti-VEGFs.

ABSTRACT: Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30-40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-? signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.

SUBMITTER: Yerramothu P

PROVIDER: S-EPMC6835305 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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New Therapies of Neovascular AMD-Beyond Anti-VEGFs.

Yerramothu Praveen P

Vision (Basel, Switzerland) 20180730 3

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30-40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development i ...[more]

PMID: 31735894

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Project description:Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

Project description:PurposeTo investigate the pharmacogenetic associations between the genetic risk variants of age-related macular degeneration (AMD) and long-term outcome after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in Korean neovascular AMD patients.MethodsThis prospective study included 394 treatment-naïve patients (394 eyes) that underwent intravitreal anti-VEGF treatment for neovascular AMD for at least 12 months. Patients were genotyped for 17 single nucleotide polymorphisms within 13 AMD-relevant genes. Initially, patients underwent three monthly injections of intravitreal ranibizumab and were retreated as needed with ranibizumab or bevacizumab. For each candidate polymorphism, genotypic associations with treatment outcome measures at months 12 and 24, including mean change in best-corrected visual acuity (BCVA) from baseline, visual gain of ≥15 letters, mean change in central subfield macular thickness (CSMT) from baseline on spectral domain optical coherence tomography (OCT), presence of fluid on OCT, and mean number of injections, were investigated using logistic or linear regression models with adjustment for non-genetic covariates.ResultsAt month 24, BCVA improved by 4.5 ± 22.5 letters and CSMT decreased by 69.4 ± 112.6 µm from baseline. Regression analysis with Bonferroni correction showed that the TT genotype for VEGFA rs3025039 was associated with a significantly higher chance of a visual gain of ≥15 letters at month 24 than other genotypes (odds ratio, 4.57; 95% confidence interval, 1.89 - 11.1; corrected p = 0.0434). As for tomographic outcome, the minor allele homozygotes for ARMS2 rs10490924 and HTRA1 rs1100638 (GG genotype for both) were associated with a larger CSMT reduction at month 12 than other genotypes, with borderline significance after Bonferroni correction (118.6 ± 132.7 µm versus 62.7 ± 89.7 µm, corrected p = 0.0656 for rs10490924; 115.7 ± 131.7 µm versus 63.6 ± 89.8 µm, corrected p = 0.0528 for rs11200638). No polymorphism showed a significant association with the number of injections.ConclusionsIn this Korean neovascular AMD cohort, treatment outcome after anti-VEGF was found to differ by the genotypes of VEGFA rs3025039, ARMS2 rs10490924, and HTRA1 rs11200638. Given more evidence of pharmacogenetic associations with the anti-VEGF agent, individualized therapeutic approaches based on genetic background could lead to optimal treatment in neovascular AMD.

Dataset Information

New Therapies of Neovascular AMD-Beyond Anti-VEGFs.

Publications

New Therapies of Neovascular AMD-Beyond Anti-VEGFs.

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