Targeting HTRA 1 for the Treatment of Age Related Macular Degeneration

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of visual impairment of the elderly in developed countries. Despite its prevalence with the aging population, its etiology and pathogenesis are poorly unde rstood and the treatment options are limited. Navigen's scientific co-founder, Kang Zhang, recently reported in SCIENCE that a polymorphism in the promoter of the gene encoding HTRA1 plays a major role in genetic susceptibility to AMD. The polymorphism (SN P rs11200638) is located 512 bp upstream of the HTRA1 transcription start site and alters a conserved AP2/SRF binding element that increases expression by approximately three fold. This human genetic discovery suggests that blocking HTRA1 activity may be a n important strategy for treating AMD. HTRA1 belongs to a family of serine proteases and is expressed in the retina, retinal pigment epithelium and in the endothelium of pathologic retinal vessels. Navigen has synthesized recombinant HTRA1 protein using a bacterial expression system. Using this protein as the immunogen, Navigen has generated polyclonal and monoclonal antibodies. In preliminary experiments, Kang Zhang and Navigen has generated a polyclonal antibody to HTRA1 that effectively inhibit pathologi c angiogensis in a murine model of hyperoxic induced retinal vascular disease. These studies provide the first proof of concept that blocking HTRA1 is an effective therapeutic strategy. Polyclonal antibodies, though effective in pilot animal studies, will not meet future regulatory and manufacturing requirements necessary to support a future. The central goal of this SBIR grant application is to advance HTRA1 monoclonal antibodies as a treatment for age-related macular degeneration. The Specific Aims are: A im 1: Generate monoclonal antibodies that recognize HTRA1. Aim 2: Examine the efficacy of monoclonal antibodies in animal models of retinal vascular disease. The major milestone for Phase I is the identification of a monoclonal antibody that recognizes HTR A1 and is effective in two animal models of opthalmic vascular disease. The Phase I application will serve as a springboard for developing a humanized HTRA1 monoclonal antibodies that is effective in reducing pathologic neovascularization of AMD and other retinal vascular diseases. These subsequent studies will form the basis of Navigen's Phase II application.