Age-related macular degeneration (AMD) is a public health problem resulting in the loss of independence in a significant number of the elderly population. The most severe form of AMD, wet AMD, is caused by the formation of new blood vessels in the choroidal region. Repeated blood leakage from these vessels damages the macula, thereby resulting in rapid irreversible vision loss. Several experimental therapeutics aimed at curtailing angiogenesis had been successful in treating wet AMD in clinical trials. However, these agents require intravitreal injections which present a significant risk of introducing infections and injuries to the eyes. Squalamine, a systemically delivered antiangiogenic aminosterol, had been shown to preserve/improve vision in 100% of patients 4 months following therapy in a phase 1/11clinical trial. Encouraged by these results, Genaera is seeking to explore squalamine analogs which may have higher potency, simpler synthesis scheme and better pharmacokinetic profile for their application in treating wet AMD. Two analogs that fit these criteria had been identified. The specific aims for this proposal are: 1. To evaluate the in vivo efficacy of squalamine and lead analogs in a rat model of choroidal neovascularization. CNV will be induced in rats by subretinal injection of Matrigel. Squalamine and analogs will be adminstered intraperitoneally daily followed by evaluation of CNV formation at the end of the studies. Studies will be carried out to evaluate squalamine and analogs' ability to prevent the formation of CNV and to regress pre-existing CNV. 2. To determine the effect of squalamine and analogs on VEGF signal transduction and integrin activity in endothelial cells. Coimmunoprecipitation and Western blotting with phosphospecific antibodies will be used to pinpoint squlamine and analogs' interference on these signaling events. The long term objective of this development program is to identify and refine safe and effective antiangiogenic aminosterols for the treatment of AMD.
Thesaurus Terms: analog, angiogenesis inhibitor, cholestane compound, drug design /synthesis /production, eye disorder chemotherapy, macular degeneration, nonhuman therapy evaluation aging, biological signal transduction, drug screening /evaluation, eye pharmacology, integrin, intraperitoneal injection, pharmacokinetics, protein structure function, vascular endothelial growth factor, vascular endothelium human tissue, immunoprecipitation, laboratory rat, western blotting
