Next generation therapeutics for macular degeneration and cancer
Novel antiangiogenic agents inspired by Cortistatin A
Age-related macular degeneration (ARMD) is a disease associated with aging that gradually destroys sharp, central vision. Approximately 10 million Americans have some vision loss that is due to ARMD. Macular degeneration is the most common cause of legal blindness in people over 60, and accounts for approximately 11.7% of blindness in the United States. About 28% of the population over age 74 is affected by this disease. ARMD is subdivided into a dry and a wet form. In the wet form of macular degeneration, abnormal blood vessels grow under the retina and macula, and cause vision loss. The wet form accounts for 10-30% of cases of ARMD. It progresses more rapidly than the dry form and vision loss is more severe. Current treatments such as Macugen, Lucentis and Avastin are administered through monthly injections directly into the eye. Complications of treatment (caused by injections) include severe inflammation within the eye, increased eye pressure, traumatic cataract, and retinal detachment or tear. Researchers at Harvard University have made novel antiangiogenic compounds that are designed to circumvent these problems.
Innovations and Advantages
Prof. E.J. Corey’s group has synthesized potent and practical antiangiogenic agents to treat macular degeneration. These compounds are small and water-soluble enough to be delivered potentially as eye-drops, hence avoiding administration by direct injection into the eye. Design of these compounds was inspired by cortistatin A, a natural antiangiogenic compound isolated in a trace component from a marine sponge, Corticulum simplex. These analogs are structurally less complex and easier to synthesize than the natural product, and functional studies have shown they inhibit capillary cell growth, migration, in vitro tube formation, and in vivo angiogenesis in the living retina of neonatal mice.
Other advantages of these novel antiangiogenic agents are summarized as follows:
• Potent antiangiogenic agents with nanomolar IC50
• Compound design inspired by cortistatin A, a natural antiangiogenic compound found in marine sponge
• Total synthesis of simplified cortistatin A analogs
• Compounds validated by in vitro angiogenesis assays
• In mouse retinal angiogenesis model, lead compound inhibits angiogenesis at a locally administered dose of 500 pmol.
• Compared to published data of cortistatin A, these novel compounds inhibit VEGF-induced cell migration of human umbilical vein endothelial cells (HUVECs) more strongly than the natural compound.
• Local administration of the lead compound in picomolar quantities inhibits retinal vessel formation in a standard animal model for wet macular degeneration.
• No observable in vitro toxicity in several cell cultures at 50 uM level.
• These water-soluble compounds can be developed as local application to treat ocular wet macular degeneration
• Potential for treatment of other angiogenesis-dependent diseases, including cancer and inflammatory conditions.
Intellectual Property Status: Patent pending
Czako B, Kurti L, Mammoto A, Ingber DE, Corey EJ. 2009. Discovery of potent and practical antiangiogenic agents inspired by cortistatin A. J Am Chem Soc. 131(25):9014-9.
Current Status in Development:
Proof-of-concept experiments: In mouse retinal angiogenesis model, lead compound inhibits angiogenesis at a locally administered dose of 500 pmol.
Corey, Elias J.
Ingber, Donald E.
For further information, please contact:
Vivian Berlin, Director of Business Development
Reference Harvard Case #3358