Age-related macular degeneration (AMD) remains a leading cause of loss-of-vision that necessitates mechanistic studies of disease and the development of new therapeutics. Early AMD progresses to later, blinding forms following one of two divergent pathways: i) Atrophic AMD is associated with degeneration and death of retinal pigment epithelium (RPE); and ii) choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. While there are treatments for CNV using anti-angiogenic drugs, there are no effective treatments for subretinal fibrosis (SRF). SRF is a complication of both end-stage and treated CNV that results in severe to profound visual impairment. To address this complication, our team invented a novel ?B-crystallin peptide nanoparticle (?BC-ELP) that markedly inhibits the progression of SRF. Elastin-like polypeptides (ELPs) are high molecular weight biocompatible biopolymers derived from human tropoelastin that retain a biologically-active fragment of the ?B-crystallin protein near the retina for extended periods, thus enabling their therapeutic efficacy. As supported by our preliminary data, we hypothesize that ?BC-ELP will prevent the progression of SRF compared to controls. We further hypothesize that the inhibitory effect of (?BC-ELP) on SRF decreases the generation of fibrosis-promoting, senescent cells and improves the regulation of mitochondrial metabolism by promoting oxidative phosphorylation. These hypotheses will be tested using the following Specific Aims:
Aim #1. Characterize ocular pharmacokinetics of intravitreal ?BC- ELP in mouse and rabbit eyes.
Aim #2. Characterize SRF and determine effect and time course of ?BC-ELP in laser model of CNV.
Aim #3. Establish the mechanistic role of senescence cells in progression of SRF and the mechanism of its inhibition by ?BC-ELP.
Aim #4. Establish the mechanistic role of mitochondrial bioenergetics and mitochondrial SMAD4 in SRF and the mechanism of its inhibition by ?BC-ELP.
Age-related macular degeneration (AMD) is the most common form of blindness in those over age 60. There is no effective treatment for sub-retinal fibrosis (SRF) which is a complication of end stage and treated CNV. This grant is focused on establishing new insights into the pathogenesis of SRF and translating this knowledge to develop novel therapeutic approaches to the disease.
