Neovascularization is a hallmark of many ocular diseases including age-related macular degeneration (AMD). AMD is a progressive and degenerative disease that affects individuals typically over the age of 60 leading to vision loss. The proangiogenic activity of VEGF contributes to the pathogenesis of neovascular AMD (nAMD). Thus, the treatment of choice for nAMD is intravitreal administration of anti-VEGF. Unfortunately, for unknown reasons a significant number of patients have poor to no response with anti-VEGF therapy for nAMD. Since anti-VEGF therapy comes with increased treatment burden and risk of vision complications including retinal atrophy and endophthalmitis, identifying patients likely to respond prior to the onset of treatment is beneficial. Our hypothesis is that Bim, a pro-apoptotic Bcl-2 family member, restrains VEGF-driven inflammation and choroidal neovascularization (CNV). In this proposal we will take the innovative approach of determining whether genetic variation in Bim expression is responsible for anti-VEGF therapy failure for nAMD.
The aims proposed here will determine whether Bim expression is required for anti-VEGF treatment to normalize endothelial cell permeability and proangiogenic properties. We will test the hypothesis that Bim expression is needed for the efficacy of anti-VEGF treatment of nAMD and determine whether Bim single nucleotide polymorphisms (SNPs) modulate the efficacy of anti-VEGF treatment. Together these studies will give us a unique perspective as to whether Bim polymorphisms impede the success of anti-VEGF therapy for nAMD. Thus, development of a biomarker will alleviate the treatment burden and potential vision risks associated with anti-VEGF therapy if no beneficial outcome will be obtained.

Public Health Relevance

Vascular endothelial growth factor (VEGF) is the key factor that drives neovascularization associated with neovascular age-related macular degeneration (nAMD), with anti-VEGF therapy being the standard treatment. Unfortunately, 30% of patients are non-responsive to this therapy for unknown reasons. The innovation of this proposal lies in our ability to determine whether genetic variation in Bim impacts the efficacy of the primary treatment modality for nAMD, anti-VEGF.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY030076-02
Application #
10077288
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2020-01-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715