Subproject for Novel Antiangiogenic Peptides for Treatment of Exudative AMD

Pathological ocular angiogenesis is a key component of several diseases that cause irreversible blindness. VEGF-neutralizing antibodies given as intravitreal injections at approximately 6 week intervals are standard of care in the treatment of exudative (wet) agerelated macular degeneration, showing that anti-angiogenic agents can slow progress of AMD, the foremost cause of blindness in the industrialized world. Injections this frequent are painful and damaging to the eye, and VEGF expression increases to resist therapy. The objective of this proposal is to discover novel anti-angiogenic agents whose mechanism is to replace the activities of natural inhibitors (TSP and PEDF) of angiogenesis which are insufficiently expressed in diseased eyes. The proposed anti-angiogenic agent is based on small synthetic peptides which potently mimic the activity of these natural inhibitor proteins. TSP- and PEDFmimetic peptides were discovered at Abbott Laboratories and Northwestern University. Unlike antibodies, these small peptides can be attached to polymers via specific chemistry to affect their slow intraocular release after intravitreal injection, with the aim of greatly reducing the frequency of treatment injections. New versions of the peptides will be needed for polymer conjugation. The goal at the end of year 5 is to file an IND for clinical trial of a new entity for treatment of wet AMD to slow the onset of blindness with less frequent intravitreal injection.