Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy
Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu, Chuanyu Guo, Tapan P. Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J. Daoud, James T. Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi
Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu, Chuanyu Guo, Tapan P. Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J. Daoud, James T. Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi
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Clinical Research and Public Health Ophthalmology

Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy

Abstract

Background To reduce the treatment burden for patients with neovascular age-related macular degeneration (nvAMD), emerging therapies targeting vascular endothelial growth factor (VEGF) are being designed to extend the interval between treatments, thereby minimizing the number of intraocular injections. However, which patients will benefit from longer-acting agents is not clear.Methods Eyes with nvAMD (n = 122) underwent 3 consecutive monthly injections with currently available anti-VEGF therapies, followed by a treat-and-extend protocol. Patients who remained quiescent 12 weeks from their prior treatment entered a treatment pause and were switched to pro re nata (PRN) treatment (based on vision, clinical exam, and/or imaging studies). Proteomic analysis was performed on aqueous fluid to identify proteins that correlate with patients’ response to treatment.Results At the end of 1 year, 38 of 122 eyes (31%) entered a treatment pause (≥30 weeks). Conversely, 21 of 122 eyes (17%) failed extension and required monthly treatment at the end of year 1. Proteomic analysis of aqueous fluid identified proteins that correlated with patients’ response to treatment, including proteins previously implicated in AMD pathogenesis. Interestingly, apolipoprotein-B100 (ApoB100), a principal component of drusen implicated in the progression of nonneovascular AMD, was increased in treated patients who required less frequent injections. ApoB100 expression was higher in AMD eyes compared with controls but was lower in eyes that develop choroidal neovascularization (CNV), consistent with a protective role. Accordingly, mice overexpressing ApoB100 were partially protected from laser-induced CNV.Funding This work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750, R01EY025705, and R01 EY27961; the Research to Prevent Blindness, Inc.; the Alcon Research Institute; and Johns Hopkins University through the Robert Bond Welch and Branna and Irving Sisenwein professorships in ophthalmology.Conclusion Aqueous biomarkers could help identify patients with nvAMD who may not require or benefit from long-term treatment with anti-VEGF therapy.

Authors

Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu, Chuanyu Guo, Tapan P. Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J. Daoud, James T. Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi

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Figure 8

Apolipoprotein B-100 plays a protective role in the development of CNV.

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Apolipoprotein B-100 plays a protective role in the development of CNV. ...
(A) ApoB100 protein level in aqueous of non-AMD control, nnvAMD, and nvAMD. Compared with that of non-AMD control, ApoB100 was significantly higher in the aqueous of patients with nnvAMD and nvAMD. Moreover, ApoB100 levels in the aqueous of patients with nnvAMD was dramatically higher than that in patients with nvAMD. (B) ApoB100 mRNA level in neurosensory retinal, RPE/choroid, and liver of both WT and ApoB mutant mice. ApoB100 levels in all 3 tissues of ApoB mutant mice are significantly higher than those from WT mice. (C and D) Laser CNV lesion size in 9-month-old (C) and 3-month-old (D) WT and ApoB100 mutant mice 7 days after treatment with laser. Scale bars: 100 μm. Individual dots represent CNV spots from choroids of 4 mice in each case. A reduction in choroidal neovascularization was observed in ApoB100 transgenic mice compared with WT mice. Results were plotted as mean ± SD. Unpaired Student’s t test was used to compare the 2 groups. *P < 0.05. (E) Vegf mRNA level in RPE/choroid from WT and ApoB mutant mice. Results were plotted as mean ± SD. P values were generated by 2-tailed Student’s t test. (F) Laser CNV comparison between WT and ApoB mutant mice 7 days following treatment with laser. A subset of mice were treated with 200 ng aflibercept on day 3 following laser treatment. n = 4 to 8 animals for each condition. Results were plotted as mean ± SD. One-way ANOVA with Tukey’s multiple comparison test was used to compare the different treatments with each other. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05; and NS, P > 0.05.