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 understood and the treatment options are limited. CalCyte's scientific co-founder, Kang Zhang, reported that polymorphisms in the promoter of the gene encoding HTRA1 plays a major role in genetic susceptibility to AMD. The polymorphism (SNP rs11200638) is located 512 by upstream of the HTRA1 transcription start site and the A risk allele is exclusively associated with a major disease haplotype which increases HTRA1 expression by approximately three fold. This human genetic discovery suggests that blocking HTRA1 activity may be an 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. Dr. Kang Zhang Lab has generated polyclonal and monoclonal antibodies against human HTRA1. In preliminary experiments, monoclonal and polyclonal antibodies to HTRA1 can effectively inhibit pathologic angiogenesis in murine models of hyperoxic induced retinal vascular disease and choroidal neovascularization. These studies provide the first proof of concept that blocking HTRA1 is an effective therapeutic strategy. Small molecule is another approach to inhibit HTRA1. Comparing with antibody, small molecule drugs have significant advantages in ease of manufacturing more cost-effectively, storing, distributing and administering. Small molecule based serine proteases inhibitors have been long reported and developed as drugs for treating specific human diseases. The central goal of this SBIR grant application is to demonstrate the HTRA1 small molecule inhibitor would serve as a new therapeutic approach for treating age-related macular degeneration and develop new/improved HTRA1 small molecule inhibitors.
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 understood and the treatment options are limited. CalCyte's scientific co-founder, Kang Zhang, reported that polymorphisms in the promoter of the gene encoding HTRA1 plays a major role in genetic susceptibility to 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. Dr. Kang Zhang Lab has generated polyclonal and monoclonal antibodies against human HTRA1. In preliminary experiments, monoclonal and polyclonal antibodies to HTRA1 can effectively inhibit pathologic angiogenesis in murine models of hyperoxic induced retinal vascular disease and choroidal neovascularization. These studies provide the first proof of concept that blocking HTRA1 is an effective therapeutic strategy. Development of specific HTRA1 small molecule inhibitors as described in this SBIR grant application will provide a new therapeutic approach for treating age-related macular degeneration.
