August 1, 2007
“I hate to be in the prediction business determining when a drug will be available,” says Don Anderson. But the center’s work is giving potential drug developers a clearer idea of the chain of events that leads to macular degeneration, and of what might be done to stop it.
The human eye is a wonder of nature that has not given up all its mysteries, at least not yet. One of these is why, with age, it so often deteriorates in a way that leads progressively to blindness. Is this disease inevitable, just the price of growing old? Or can it be stopped?
Scientists with UCSB’s Center for the Study of Macular Degeneration (CSMD) believe it can be stopped and have been working toward that goal for more than a decade. Focusing on the cells, proteins and genetic factors that affect the aging eye, they have shed light on what really happens when sight declines. In the process, they are showing the way toward drugs that could eventually prevent or reverse this all-too-common condition.
“I hate to be in the prediction business determining when a drug will be available,” says Don Anderson, a research biologist and director of CSMD. But the center’s work is giving potential drug developers a clearer idea of the chain of events that leads to macular degeneration, and of what might be done to stop it. Anderson says CSMD has achieved breakthroughs in basic research that now enable it to move to the “application phase” – finding ways to put that research to work.
CSMD, set up in 1995 as a research unit within UCSB’s Neuroscience Research Institute, focuses on age-related macular degeneration, usually referred to as AMD. It had a more informal start earlier in the decade in the sharing of ideas between Anderson and two other scientists. One of them, research biologist Lincoln V. Johnson, was at the University of Southern California and came to UCSB in 1995. The other, Gregory Hageman, had worked with Johnson in post-doctoral research during the 1980s and then went to the University of Iowa, where he is a professor of ophthalmology and visual science. Johnson says the three shared a common interest in macular degeneration and started a close collaboration that has continued to this day.
A Timely Target
Why macular degeneration? “It was an acute and growing problem in society because of the aging population,” says Johnson.
The disease was (and is) a timely target. According to the National Eye Institute, AMD is the leading cause of irreversible blindness in developed countries, and is widespread among the elderly in this country. The NEI estimated in 2004 that more than 1.7 million Americans had advanced AMD with vision loss.
Another 7.3 million had intermediate AMD and were at substantial risk of losing vision. The aging of the Baby Boomers will make the disease even more common unless more effective treatments for it are found. The NEI projected that 2.9 million would have advanced AMD by 2020.
AMD attacks the macula (Latin for “spot”), an area on the retina that is dense with cone cells designed for high acuity. Its breakdown affects the center of vision, impairing the ability to read, drive or do anything else that requires visual focus. With so little known about the cause of AMD, scientists have been limited to trial-and-error methods for treating symptoms. For early AMD, Vitamin E and antioxidants seem to do some good. Drugs also have been developed to treat the “wet” form of AMD, marked by abnormal growth of blood vessels. These medicines are effective, but they must be injected regularly into the eye. They also catch the disease at a late stage and they only help one part of the AMD population. Anderson says only about 10% to 15% of those diagnosed with early AMD eventually get the “wet” form.
Anderson, Johnson and Hageman took a different line of attack, seeking to understand the molecular and cellular basis of AMD so that drugs might be developed to keep it from starting in the first place. The three started by focusing on the composition of drusen (German for “geodes”), the yellow or white deposits that accumulate at the macula in early AMD. Screening a large number of human eyes using antibodies, they found that drusen contained vitronectin, a protein that regulates the complement cascade, a chain reaction in which proteins of the immune system identify and kill microbes.
Upper figure: Microscopic image of drusen deposits that characterize age-related macular degeneration. Spherical structures embedded in drusen contain beta amyloid, a peptide associated with plaques in the brains of patients with Alzheimer's disease. Middle figure: Higher resolution image showing the concentric ring-like structure of the amyloid spheres. Lower figure: A molecular model of the spheres based upon their structural appearance in the electron microscope.
That was the initial pathway discovery for us,” says Anderson. It suggested that the formation of drusen may be the result of an immune response. They eventually found drusen to contain at least a dozen proteins that were associated with the complement system, as part of the cascade or in regulating it.
Focusing on Factor H
In 2001 and 2002, they published articles laying out these results. “We concluded that drusen were actually consequences of local inflammation,” says Anderson. “That set the stage for targeting the complement system as a likely factor in AMD.” Working with a number of other U.S. and European scientists including Rando Allikmets, a Columbia University geneticist specializing in eye disorders, they analyzed the genetic basis of the complement proteins in drusen and homed in on one in particular – the complement regulator protein Factor H. They found that a variant of the Factor H gene, present in about 20% to 25% of Americans of European origin, was associated with a high susceptibility to AMD. Those having one copy of the variant were two to three time more susceptible to the disease; two copies raised the risk by a factor of six or seven.
In 2005, Hageman, Anderson Johnson, Allikmets and their co-workers published these results, Anderson says this news of a genetic connection to AMD developed into a “fairly dramatic media event,” with Hageman briefing members of Congress and their staffs on the discovery, and federal health officials heralding it as a validation of the Human Genome Project.
Applying this knowledge to the prevention and cure of AMD could be a long and uncertain process. But Anderson and Johnson say several therapeutic routes have emerged from the CSMD’s research. Since AMD is linked to inflammation, non-steroidal anti-inflammatory drugs (NSAIDs – a class that includes aspirin and ibuprofin) might be useful in treating the disease. Gene therapy is another option. Anderson says a virus might be programmed “to coax the liver into making good Factor H” (the liver is a major source of complement proteins). It also may be possible to develop a drug that mimics the action of good Factor H. With any of these approaches, Anderson says it would not be necessary to prevent AMD permanently, just to postpone it to a point beyond the typical lifespan. “If you could delay the disease by 10 or 20 years, you would effectively cure it,” he says.
The center’s work on AMD may be just a starting point for understanding and treating some of the most common diseases of aging. Anderson says the Factor H research may prove relevant wherever there is an “inflammatory component,” as is the case in Alzheimer’s and atherosclerosis. CSMD also has plenty of knowledge-producing potential in its technology. Helped by funding from the National Eye Institute, it has “managed to put together an impressive genomics and proteomics laboratory,” says Dennis Clegg, professor and chairman of Molecular, Cellular and Developmental Biology at UCSB.
Clegg, a neurobiologist who specializes in cell adhesion and retinal development, has his lab next-door to CSMD and says he collaborates with it “quite heavily” (he is also a CSMD member and works with Johnson on research into the use of embryonic stem cells to replace damaged eye cells). The CSMD lab has advanced equipment for automated genomic analysis, enabling researchers to look at the process of gene expression – the conversion of a gene’s DNA sequence into RNA and proteins – at any stage of a disease. This is “an invaluable technique to have in your repertoire,” Clegg says. Likewise for the CSMD as a whole. The center offers a model of long, successful collaboration that may prove to be invaluable for many other researchers fighting many other diseases.