Purchase this article with an account.
Rania Sulaiman Sulaiman, Halesha Dhurvigere Basavarajappa, Bit Lee, Hyeongjun Lee, Seung-Yong Seo, Timothy William Corson; A small molecule pharmacotherapy ameliorates laser-induced choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2470.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Choroidal neovascularization leads to vision loss in wet age-related macular degeneration (AMD), a major cause of blindness in the elderly. Biologics targeting vascular endothelial growth factor (VEGF) signaling are standard treatments for this disease. However, such biologics are associated with ocular and systemic side effects, and some patients are refractory. Therefore, there is a need for small molecule treatments for wet AMD. We previously synthesized the anti-angiogenic homoisoflavanone, cremastranone, and showed effects on human retinal endothelial cells. A synthetic derivative of cremastranone, SH-11037, showed remarkable potency and selectivity in vitro, as well as anti-angiogenic efficacy in vivo in the oxygen induced retinopathy model. Here, we set out to test the efficacy of intravitreally injected SH-11037 in the laser-induced choroidal neovascularization (L-CNV) model and to demonstrate the absence of ocular toxicity.
Eight week old C57BL/6J mice received laser burns to the choroid and intravitreal injections of SH-11037 (1 µM), vehicle, or anti-VEGF antibody. In vivo monitoring of lesion volume was performed at day 7 using optical coherence tomography (OCT). On post-laser day 14, eyes were enucleated and flatmount choroidal layers were stained with agglutinin for ex-vivo quantification. Z-stack confocal micrographs were used with ImageJ software to calculate the average lesion volume per eye. Toxicity of intravitreally injected SH-11037 was assessed by histology and immunohistochemistry
SH-11037 significantly suppressed angiogenesis in the L-CNV model compared to vehicle treatment and was comparable to anti-VEGF antibody. The average volume of CNV lesions was calculated from the OCT images, P<0.01, as well as from Z-stack confocal images, P< 0.001. Moreover, 3- and 14-day toxicity studies established the absence of changes in retinal morphology after intravitreal injection of SH-11037 up to 100 µM final concentration. Additionally, SH-11037 did not cause any retinal injury, apoptosis, or inflammation, as evidenced by staining for glial fibrillary acidic protein, cleaved caspase-3, and monocyte chemotactic protein-1, respectively.
These data demonstrate the strong anti-angiogenic potential of SH-11037 for L-CNV in vivo, in the absence of ocular side effects. Thus, this molecule is an exciting lead for the development of a small molecule treatment for wet AMD.
This PDF is available to Subscribers Only