New Therapeutic Strategy for Neovascular AMD

Chenghua Gu, DVM, PhD
Harvard Medical School (Boston, MA)
Year Awarded:
2013
Grant Duration:
July 1, 2013 to June 30, 2015
Disease:
Macular Degeneration
Award Amount:
$120,000
Grant Reference ID:
M2013127
Award Type:
Standard
Award Region:
US Northeastern
This grant is made possible by a bequest from the Rasmussen Family Trust.

The Role of Semaphorin 3E Signaling in Neovascular AMD

Summary

Patients with neovascular age-related macular degeneration (wet AMD) have benefited from therapies that inhibit the formation of new blood vessels in the retina. These medications on the market, including pegaptanib (Macugen®), ranibizumab (Lucentis®), bevacizumab (Avastin®), and EYLEA®, directly bind VEGF, a protein that stimulates blood vessel formation in the eye. Dr. Gu’s team proposes to improve the therapies for wet AMD by finding novel therapies that could be used alone or in combination with the existing therapeutics. Dr. Gu’s laboratory has recently identified a new signaling pathway through the proteins Semaphorin 3E (Sema3E) and Plexin-D1 that inhibits the function of VEGF. More importantly, this pathway only functions in the newly formed abnormal blood vessels, but not in the normal blood vessels. Thus, through searching for new peptides and drugs that target this pathway, the team will discover novel therapeutic agents that expand the repertoire in fighting AMD and improve the quality of life for patients suffering from AMD.

Details

Existing antiangiogenic therapies targeting VEGF have provided significant benefits to patients with wet AMD. However, even with scheduled monthly injections, many patients don’t achieve substantial improvement in visual acuity. In addition, agents that directly negate VEGF may carry a risk of prolonged systemic exposure, which could increase the possibility of serious side effects. Novel therapies are still needed for better control of wet AMD and regaining visual acuity. Dr. Gu’s laboratory has recently discovered a novel molecular signaling cascade that regulates new blood vessel growth via an intriguing reciprocal interaction between VEGF and the traditional axon (nerve cell) guidance ligand-receptor signaling of Sema3E and Plexin-D1. They found that VEGF induces Plexin-D1 expression and the Sema3E-Plexin-D1 signaling in turn inhibits the activity of VEGF-induced Notch protein signaling to control new retinal blood vessel growth. Importantly, in comparison to the VEGF receptor which is universally expressed in all blood vessels, the team found that Plexin-D1 is only expressed in actively sprouting vessels, and is dramatically downregulated in established blood vessels. New therapies targeting the Sema3E-Plexin-D1 signaling pathway could provide novel blood vessel growth-blocking therapies that offer superior specificity, and could be used alone or in combination with the VEGF antagonists.

Compared to anti-VEGF treatments, treatments targeting Sema3E-Plexin-D1 signaling would potentially be superior because Plexin-D1 is only expressed in abnormally-formed vessels but not in normal vessels. Accordingly, this future, targeted treatment should have fewer side effects than treatments that block all VEGF. Dr. Gu’s team is incredibly excited to be part of the development of these novel treatments, and cannot sufficiently express their gratitude to those willing to support this work.

About the Researcher

Dr. Gu is an Assistant Professor of Neurobiology at the Harvard Medical School. She has previously trained as a postdoctoral fellow at Johns Hopkins University School of Medicine, and completed her doctoral studies at Weill Cornell Medical College. Dr. Gu's laboratory focuses on the molecular mechanisms governing the neural and vascular network formation, and neuro-vascular interactions. Her research team employs a combination of mouse genetics, imaging, biochemistry, cell biology, and computational modeling approaches. In addition to her BrightFocus award, Dr. Gu is the recipient of the prestigious Sloan award for young investigators, the Basil O’Connor Starter Scholar from the March of Dimes Foundation, Klingenstein award in Neurosciences, Whitehall foundation award, and new scholar award in aging from the Ellison Medical foundation.