There are a number of eye diseases, many leading to blindness, in which ocular neovascularization occurs. These include (1) diabetic retinopathy, (2) neovascular glaucoma (3) inflammatory diseases, and (4) ocular tumors (e.g. retinoblastoma). At present, the treatment of these diseases, especially once neovascularization occurs, is often inadequate and blindness frequently results. Thus it is conceivable that an inhibitor of neovascularization could have an important therapeutic role in relieving the course of these diseases, particularly ocular tumors. Such an inhibitor might also provide a useful tool with which to better study the etiology of these diseases. We have isolated and partially purified a vascular inhibitory factor from scapular cartilage. This substance inhibited the vascular response to V2 carcinoma in the rabbit cornea when administered locally by a polymer implant which continuously released the factor. This inhibitor has been infused regionally into mice with B16 melanoma in the conjunctiva and into rabbits carrying V2 carcinoma in the cornea. In both systems, neovascularization and tumor growth was stopped during the period of infusion. No toxic effects to any animals were observed. The yield of the inhibitor has been increased by exploring other sources of cartilage, in particular, shark cartilage. The polymer- cornea assay technique has been refined and improved. We have also isolated a potent new inhibitor of angiogenesis consisting of a hexasaccharide of heparin combined with cortisone. These initial studies in our laboratory have provided the first evidence that naturally occurring inhibitors of ocular neovascularization exist and can be used to inhibit at least some forms of neovascularization in the eye. Having demonstrated this important biological activity, the specific aims of our proposed study are to: 1. Purify and characterize the cartilage inhibitor. 2. Purify and characterize the heparin hexasaccharide inhibitor. 3. Develop more rapid and sensitive assays for testing inhibitors of neovascularization.
