The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis. Pathological retinal or choroidal neovascularization lead to visual loss in diabetic retinopathy (DR) and age related macular degeneration (ARMD), respectively. While inhibition of abnormal angiogenesis would not necessarily cure the underlying diseases, it would preserve vision by preventing complications associated with neovascularization such as hemorrhage and edema. We have been studying the anti-angiogenic activity of fragments of tryptophanyl-tRNA synthetase (TrpRS). In normal human cells TrpRS exists as both the full length form and a truncated form (mini-TrpRS) in which an amino-terminal domain is deleted due to alternative splicing of the pre-mRNA. This latter form is preferentially synthesized in cells exposed to interferon-w. Further truncation of mini-TrpRS results in a 42 kD form (T2) that is the most potent of the angiostatic forms of TrpRS evaluated to date. In this application we propose to further characterize the anti-angiogenic activity of TrpRS fragments and identify a candidate drug and delivery system for use in clinical trials of neovascular eye diseases. Specifically, we will: (1) examine the physiological role of TrpRS fragments in the regulation of normal and abnormal ocular angiogenesis; (2) identify and characterize the retinal receptor to which these fragments bind; (3) characterize the structural aspects of TrpRS fragments with anti-angiogenic activity and use this information to model small molecular antagonists with similar activity; (4) develop viral-, cell- and targeted liposome-based vectors for the delivery of T2 to inhibit ocular neovascularization in a variety of animal models; and (5) begin pharmacokinetic and toxicology studies on these vector, recombinant protein and/or small molecule therapeutics as a first step towards human clinical trials for the treatment of neovascular eye diseases such as neovascular ARMD, proliferative DR and rubeotic glaucoma.
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