Discovery of key molecular target in age-related macular degeneration

Jun 15 2009

A team of researchers led by Dr. Jayakrishna Ambati at the University of Kentucky has discovered a biological marker for neovascular age-related macular degeneration (AMD), the leading cause of blindness in older adults.

The marker, a receptor known as CCR3, shows strong potential as a means for both the early detection of the disease and for preventive treatment. The findings were reported in an article published online Sunday by the prestigious journal Nature.

"This is a major paradigm shift in macular degeneration research," said Ambati, a professor of physiology, professor and vice-chair of ophthalmology and visual sciences, and the Dr. E. Vernon and Eloise C. Smith Endowed Chair in Macular Degeneration at the UK College of Medicine. "With CCR3, we have for the first time found a unique molecular signature for the disease. This brings us closer than we have ever been to developing a clinical diagnostic tool to discover and treat the disease early, before vision is lost."

Neovascular (or "wet-type") macular degeneration is caused by choroidal neovascularization (CNV) - the invasive growth of new blood vessels in the thin vascular layer that provides nourishment and oxygen to the eye. Central vision loss occurs when these abnormal blood vessels invade the retina, the light-sensitive tissue that lines the inner surface of the eyeball.

"Once the vessels invade the retina, the horse has already left the barn," Ambati said. "At that point, drugs can slow the process, but irreparable damage has often already been done. This is why finding a means for early detection and intervention is so important."

Drs. Atsunobu Takeda, Judit Z. Baffi, Mark E. Kleinman, Won Gil Cho and other researchers in the Ambati laboratory discovered that CCR3 - a molecule also implicated in inflammatory processes - is expressed on the surface of CNV vessels in humans but is absent from normal vascular tissue.

"CCR3 chemokine receptor is known to be a key player in the allergic inflammation process, but Dr. Ambati's studies have now identified CCR3 as a key marker of the CNV process involved in AMD. If researchers can determine why CCR3 is expressed in the CNV of AMD patients, they could further understand AMD disease progression," said Dr. Grace L. Shen, director of the ocular immunology and inflammation program at the National Eye Institute.

Ambati's research team was able to detect these same abnormal blood vessels in the living eyes of mice by attaching anti-CCR3 antibodies to tiny semiconductor nanocrystals called "quantum dots" and injecting these into the mice. The antibodies cause the quantum dots to attach to CCR3 on the surface of the abnormal blood vessels, making them visible with conventional ocular angiography techniques, even before they have penetrated the retina. This was not possible before.

"This is an exciting discovery for the millions of people at risk of developing wet macular degeneration, because this new imaging technology introduces the possibility of detecting pathological neovascularization before retinal damage and vision loss occur," said Dr. Stephen J. Ryan, professor of ophthalmology at the University of Southern California and member of the National Academy of Sciences' Institute of Medicine.

The research team discovered that CCR3 not only provides a unique signature for CNV, but the gene actively promotes the growth of these abnormal blood vessels in the eye. Thus the same anti-CCR3 antibodies used to detect CNV could potentially be useful as a clinical treatment to prevent macular degeneration.

The early results look promising. Treatment with anti-CCR3 antibodies reduced CNV in mice by about 70 percent, as opposed to 60 percent with VEGF-based treatments currently in clinical use. Ambati says Phase I clinical trials are not far off.

"The identification of CCR3 on the endothelial cells of CNV in human AMD is a major breakthrough," said Dr. Patricia A. D'Amore, professor of ophthalmology at Harvard Medical School. "The preclinical data is very exciting and suggests that targeting CCR3 may be the basis of the next generation of targeted anti-angiogenesis therapy for wet AMD."

Ambati's paper, "CCR3 is a target for age-related macular degeneration diagnosis and therapy," was released online today and will be printed in an upcoming issue of Nature.

Age-related macular degeneration is the leading cause of blindness in older adults in the industrialized world, affecting some 10-12 million people in the United States - more than all cancers combined and about twice as many as Alzheimer's disease. Nationwide, about 250,000 new cases of CNV are reported annually.

This work was supported by research grants from the National Eye Institute of the National Institutes of Health and an unrestricted grant from Research to Prevent Blindness. Dr. Ambati is also supported by a Doris Duke Distinguished Clinical Scientist Award and the Burroughs Wellcome Translational Research Clinical Scientist Award. Key collaborators in the study include Drs. Marc Rothenberg (Cincinnati Children's Hospital), M. Elizabeth Hartnett (UNC-Chapel Hill), Craig Gerard (Children's Hospital, Boston), Salvatore Grisanti (University of Luebeck), and Justine Smith (Casey Eye Institute).