Protein therapeutics for the chorioretina

National Eye Institute

Investigators

Linked publications & trials

Abstract

We completed the development of a novel imaging technique for the evaluation and quantification of laser-induced choroidal neovascularization (CNV) complexes in rodents. Using this technique we continued evaluating the efficacy of PEDF-derived peptides and other antiangiogenic factors on experimental CNV complex development. The route of delivery was a subconjunctival injection of protein solution. PEDF solutions were injected before and after laser injury or even after vessels had been formed. We found that PEDF, small peptides derived from the PEDF amino-end region, and angiostatin inhibited CNV development. The efficacy of PEDF subconjunctival injections on regression of fully developed vessels was observed.[unreadable] [unreadable] We continued the studies on the effects of extracellular matrix degrading enzymes on PEDF and PEDF-derived peptides. The MMP-2 enzyme activity on itself and on PEDF was pH sensitive. We also continued studying the effects of doxycyclin (bacteriostatic antibiotic with anti-metalloproteolytic effects) on CNV. Doxycyclin administered orally inhibited experimental CNV complex development. We determined the levels of matrix metalloproteinases type 2 and 9 and of PEDF in serum of doxy treated animals. We found that PEDF levels had increased with doxycyclin treatments.[unreadable] [unreadable] We evaluated potential matrixes for the ocular delivery of proteins. Subconjunctival injections of a temperature sensitive copolymer containing fluoresceinated ovalbumin (a serpin closely related to PEDF) were performed in rat eyes. Microscopy of frozen cross sections of eyes showed detection of fluorescein signal distributed in the sclera, choroid, RPE and retina even at 14 days post-injection.[unreadable] [unreadable] PEDF stimulates the phospholipase A activity of a PEDF receptor, and the release of DHA from RPE cells. The effects of dietary DHA in experimental CNV in vivo were examined. We measured the volumes of CNV complexes of rodents subjected to DHA deficient and adequate diets. CNV complex volumes in animals with the adequate diet were significantly decreased relative to those in animals with the DHA deficient diet.