Inefficacy of Anti-VEGF Therapy Reflected in VEGF-mediated Photoreceptor Degeneration

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2024 May 1

PMID 38689803

Authors

Xin Xu

Ni Han

Fangkun Zhao

Ruoyue Fan

Qingguo Guo

Xuefei Han

Ying Liu

Guangzuo Luo

Affiliations

Soon will be listed here.

Abstract

Retinal neovascularization (RNV) is primarily driven by vascular endothelial growth factor (VEGF). However, current anti-VEGF therapies are limited by short half-lives and repeated injections, which reduce patient quality of life and increase medical risks. Additionally, not all patients benefit from anti-VEGF monotherapy, and some problems, such as unsatisfactory vision recovery, persist after long-term treatment. In this study, we constructed a recombinant adeno-associated virus (AAV), AAV2-SPLTH, which encodes an anti-VEGF antibody similar to bevacizumab, and assessed its effects in a doxycycline-induced mouse model of RNV. AAV2-SPLTH effectively inhibited retinal leakage, RNV progression, and photoreceptor apoptosis in a mouse model. However, proteomic sequencing showed that AAV2-SPLTH failed to rescue the expression of phototransduction-related genes, which corresponded to reduced photoreceptor cell numbers. This study suggests that anti-VEGF monotherapy can significantly inhibit RNV to some extent but may not be enough to save visual function in the long term.

References

Terasaki H, Sakamoto T, Shirasawa M, Yoshihara N, Otsuka H, Sonoda S . Penetration of bevacizumab and ranibizumab through retinal pigment epithelial layer in vitro. Retina. 2015; 35(5):1007-15. DOI: 10.1097/IAE.0000000000000428. View

Hussain R, Shaukat B, Ciulla L, Berrocal A, Sridhar J . Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration. Drug Des Devel Ther. 2021; 15:2653-2665. PMC: 8232378. DOI: 10.2147/DDDT.S295223. View

Toutounchian S, Ahmadbeigi N, Mansouri V . Retinal and Choroidal Neovascularization Antivascular Endothelial Growth Factor Treatments: The Role of Gene Therapy. J Ocul Pharmacol Ther. 2022; 38(8):529-548. DOI: 10.1089/jop.2022.0022. View

Lamb T . Evolution of the genes mediating phototransduction in rod and cone photoreceptors. Prog Retin Eye Res. 2019; 76:100823. DOI: 10.1016/j.preteyeres.2019.100823. View

Do D, Rhoades W, Nguyen Q . PHARMACOKINETIC STUDY OF INTRAVITREAL AFLIBERCEPT IN HUMANS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Retina. 2019; 40(4):643-647. DOI: 10.1097/IAE.0000000000002566. View

Tian X, Zheng Q, Xie J, Zhou Q, Liang L, Xu G . Improved gene therapy for MFRP deficiency-mediated retinal degeneration by knocking down endogenous bicistronic and transcript. Mol Ther Nucleic Acids. 2023; 32:843-856. PMC: 10238587. DOI: 10.1016/j.omtn.2023.05.001. View

Miller J, Le Couter J, Strauss E, Ferrara N . Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2012; 120(1):106-14. DOI: 10.1016/j.ophtha.2012.07.038. View

Campbell M, Doyle S . Current perspectives on established and novel therapies for pathological neovascularization in retinal disease. Biochem Pharmacol. 2019; 164:321-325. DOI: 10.1016/j.bcp.2019.04.029. View

Wells J, Glassman A, Ayala A, Jampol L, Aiello L, Antoszyk A . Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372(13):1193-203. PMC: 4422053. DOI: 10.1056/NEJMoa1414264. View

10.

Sarkar A, Jayesh Sodha S, Junnuthula V, Kolimi P, Dyawanapelly S . Novel and investigational therapies for wet and dry age-related macular degeneration. Drug Discov Today. 2022; 27(8):2322-2332. DOI: 10.1016/j.drudis.2022.04.013. View

11.

Meyer N, Chapman M . Adeno-associated virus (AAV) cell entry: structural insights. Trends Microbiol. 2021; 30(5):432-451. PMC: 11225776. DOI: 10.1016/j.tim.2021.09.005. View

12.

Del Amo E, Rimpela A, Heikkinen E, Kari O, Ramsay E, Lajunen T . Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res. 2016; 57:134-185. DOI: 10.1016/j.preteyeres.2016.12.001. View

13.

Fleckenstein M, Keenan T, Guymer R, Chakravarthy U, Schmitz-Valckenberg S, Klaver C . Age-related macular degeneration. Nat Rev Dis Primers. 2021; 7(1):31. DOI: 10.1038/s41572-021-00265-2. View

14.

Krohne T, Liu Z, Holz F, Meyer C . Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012; 154(4):682-686.e2. DOI: 10.1016/j.ajo.2012.03.047. View

15.

Himasa F, Singhal M, Ojha A, Kumar B . Prospective for Diagnosis and Treatment of Diabetic Retinopathy. Curr Pharm Des. 2021; 28(7):560-569. DOI: 10.2174/1381612827666211115154907. View

16.

Chatziralli I, Sergentanis T . Ocular gene therapy for neovascular AMD: a new era?. Lancet. 2017; 390(10108):2139-2140. DOI: 10.1016/S0140-6736(17)32447-9. View

17.

Wilkinson C, Ferris 3rd F, Klein R, Lee P, Agardh C, Davis M . Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003; 110(9):1677-82. DOI: 10.1016/S0161-6420(03)00475-5. View

18.

Tsai C, Chen C, Wu H, Liao C, Hua K, Hsu C . Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients. Int J Med Sci. 2022; 19(5):893-900. PMC: 9149650. DOI: 10.7150/ijms.73489. View

19.

Xie Y, Wang J, He Y, Yu X, Zheng Q, Ling C . The use of melittin to enhance transgene expression mediated by recombinant adeno-associated virus serotype 2 vectors both in vitro and in vivo. J Integr Med. 2022; 21(1):106-115. DOI: 10.1016/j.joim.2022.10.003. View

20.

Khanani A, Thomas M, Aziz A, Weng C, Danzig C, Yiu G . Review of gene therapies for age-related macular degeneration. Eye (Lond). 2022; 36(2):303-311. PMC: 8807824. DOI: 10.1038/s41433-021-01842-1. View