Eyeworld

EW RETINA 118 by Matt Young and Gloria Gamat EyeWorld Contributing Writers Based on previous investiga- tions, membrane barriers and the drug-destructive mechanism of the ocular surface were found to be the major limiting factors that prevent- ed the development of eye drop treatment for retinal disorders. In addition, because intraocular fluid normally flows from vitreous to aqueous, there is limited diffusion of topical drops to the retina when de- livered to the eye's anterior chamber. That might not be the case with Vasotide, according to the research team. "A small molecule given topical- ly, however, can effectively reach the posterior ocular tissues via the con- junctiva, with passage subsequently through sclera, choroid, RPE, and retina," they reported. "One could speculate that this delivery route may be augmented in the future by taking advantage of endogenous carrier systems, such as harnessing the high iron-transferrin receptor expression on conjunctival cells by applying nanoparticles that are surface-coated with transferrin, or perhaps our recently described iron-mimic peptide motif," they explained. While the application of eye drop drug therapy has been found successful in ROP mouse models and laser-induced monkeys with Prototype drug candidate will potentially target some retinal disorders in a less invasive way T he central involvement of pathological angiogenesis is the common denomina- tor among retinal diseases, such as retinopathy of prematurity (ROP) in babies, diabetic macular edema (DME) in adults, and age-related macular degeneration (AMD) in the elderly. When vascular endothelial growth factor (VEGF) became under- stood as a key component in normal and pathological vascular growth, the knowledge led to the develop- ment of anti-VEGF agents, which came to revolutionize the way clinicians approach the treatment of retinal diseases. While currently available anti- VEGF agents are doing wonders, not all patients react positively. Some patients develop resistance and in other cases, the required repeated injections of these large molecule anti-VEGFs directly into the eye can be very expensive and clinically problematic. "Current anti-angiogenic treatments for retinal diseases are primarily administered through the intravitreal route, which has its risks and complications, as well as the problems of patient discomfort and thus non-compliance," said Stephen Teoh, FRCSEd, senior consultant ophthalmologist, and director of vitreoretinal surgery, Eagle Eye Centre, Singapore. Introducing Vasotide In the October 2015 issue of Science Translational Medicine, researchers from Harvard reported their findings on the effect of a peptide drug called Vasotide (which can be delivered via eye drops) on blood vessel over- growth in the retinas of different an- imal models of retinal diseases such as retinopathy of prematurity (ROP) and age-related macular degenera- tion (AMD). "We have evaluated a small cy- clic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys) [D(CLPRC)], and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors VEGFR-1 and neuropilin-1 (NRP-1)," reported Richard Sidman, MD, Bullard professor of neuropa- thology, Harvard Medical School, and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, the study's lead investigator. "Delivery of Vasotide via either eye drops or intraperitoneal injec- tion in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of ROP decreased retinal angiogenesis in all three animal models," the research- ers reported. Vasotide, the prototype drug candidate, according to the research- ers, is a promising new dual receptor inhibitor of the VEGF ligand that can potentially be translated into a safer, less-invasive treatment application that will target patholog- ical angiogenesis in retinal disorders. "Vasotide is a novel drug that has been shown to inhibit angiogen- esis in mouse and monkey models of retinal diseases by an eye drop vehi- cle," Dr. Teoh explained. "Because of the shortcomings of currently avail- able anti-VEGF agents, a simpler, saf- er and similarly efficacious route of delivery will no doubt revolutionize treatment and improve patient com- pliance and outcomes," he added. How Vasotide works Currently approved treatments for human angiogenic retinal diseas- es include pegaptanib (Macugen, Bausch + Lomb, Bridgewater, N.Y.), ranibizumab (Lucentis, Genentech, South San Francisco), and afliber- cept (Eylea, Regeneron, Tarrytown, N.Y.), Dr. Teoh noted. "In addition, bevacizumab [Avastin, Genentech], although used off-label and not approved by the U.S. Food and Drug Administration (FDA) for retinal diseases, is also widely used interna- tionally; these drugs act mainly on VEGF-A, that binds mainly to VEGF receptor-2," he explained. On the other hand, Vasotide is the only external agent that binds the 2 receptors: VEGFR-1 and neuropilin-1 (NRP-1), potentially providing an additional mechanism of anti-angiogenesis. "Vasotide may be useful in patients who either are unrespon- sive to the currently used agents or become resistant during repeated intraocular injections," Dr. Sidman and colleagues reported. "In addi- tion, although NRP-1 and VEGFR-1 have been less intensively studied than VEGFR-2, evidence suggests that they may regulate angiogenesis via different mechanisms of action," they noted. The current research by Dr. Sidman and colleagues, Dr. Teoh said, demonstrated the positive response of animal models of ROP and AMD to Vasotide. "As research has yet to be per- formed on human subjects, it would be interesting to show if the drug has similar effects in humans," he said. "Our results also indicate that Vasotide may be a valuable alter- native to the present therapeutic agents that are injected intravitre- ally because the peptidomimetic's administration routes are far simpler and less likely to damage the retina iatrogenically," the researchers reported. Novel peptide drug for treatment of retinal diseases on the horizon March 2016 Fundus photo and OCT of exudative AMD (left); fundus photo and OCT after treatment with intravitreal aflibercept (right) Source: Stephen Teoh, MD

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