Protein therapeutics for the chorioretina

National Eye Institute

Investigators

Linked publications & trials

Abstract

Pigment epithelium-derived factor (PEDF) is an extracellular multifunctional serpin with neurotrophic, antiangiogenic and antitumorigenic activities. Work of this research group is aimed at identifying route, dose and delivery devices for the safe and stable administration of effective PEDF peptide agents in the eye of animal models related to chorioretina diseases. The goal of this study is the molecular design of potent PEDF peptides for ocular treatment to achieve altered binding specificity and prevention of side effects. [unreadable] [unreadable] We studied the structure-function relationships of PEDF?s antiangiogenic activity. We compared the efficacy of PEDF peptides, other antiangiogenic factors and serpins in an in vivo assay developed in our laboratory for the evaluation and quantification of chroroidal neovascularization (CNV) complexes in rodents. CNV lesions were induced with laser energy, and the morphology and volume of the lesions evaluated in choroid/RPE flat mounts by confocal microscopy using 3-D reconstructions. The route of protein delivery was a subconjunctival injection of a given concentration of peptide or protein solution. We found that PEDF and 34-mer, a small PEDF peptide towards the amino-end region, and angiostatin inhibited CNV development.[unreadable] [unreadable] We evaluated doxycyclin, a bacteriostatic antibiotic with anti-metalloproteolytic effects, for its potential antiangiogenic effects (in collaboration with Debbie Carper?s laboratory, NEI). Doxycyclin was administered orally and had a negative effect in CNV complex development. [unreadable] [unreadable] Experiments on the effects of extracellular matrix degrading enzymes on PEDF and PEDF-derived peptides showed that the MMP-2 enzyme degraded PEDF in PBS but only nicked the polypeptide in Tris buffers.