Abstract
Purpose :
Choroidal neovascularization (CNV) is a hallmark of neovascular (exudative) age-related macular degeneration (nAMD). In the aging population, aberrant growth of choroidal vessels through the Bruch’s membrane, termed CNV, results in loss of central vision. Bim is a pro-apoptotic Bcl-2 family member and is essential for apoptosis of cells exposed to decreased pro-survival factors such as VEGF (anti-VEGF) or drugs such as dexamethasone. We proposed reduced levels of Bim contributes to lack of responsiveness to anti-VEGF treatment. Here we assessed various CNV therapies to determine whether Bim expression was essential for their efficacy.
Methods :
The mouse model of laser induced CNV was used to assess the impact of anti-VEGF, ABT898 (thrombospondin-1 mimetic peptide), propranolol, and anti-CTGF (connective tissue growth factor) in preventing CNV in 3-month-old Bim +/+ and Bim -/- mice, or Bimflox/flox crossed with Lyz2-Cre (BimMP). The degree of neovascularization was assessed by immunostaining of flatmounts from control or treated mice two weeks after laser-treatment. The area of neovascularization was determined using ImageJ software.
Results :
Although anti-VEGF treatment mitigated CNV in Bim +/+ (wild-type) mice it failed to alleviate CNV in Bim-/- mice or mice lacking Bim expression in macrophages (BimMP). The ABT898 also significantly reduced CNV in Bim +/+ mice but did not alleviate CNV in Bim -/- or BimMP mice. In contrast, propranolol and anti-CTGF effectively reduced CNV in the absence of Bim.
Conclusions :
Reduced Bim levels due to unique polymorphisms and/or deletions may result in an incomplete response to therapies that utilize a similar intrinsic death pathway to temper inflammation, CNV and fibrosis.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.