Any Given Wednesday:
Vision Researcher Keeps Patients in Focus

By Jason Socrates Bardi

Today, like most Wednesdays in the Scripps Clinic's Anderson Outpatient Pavilion adjacent to on the lower level of the Green Hospital, things are a bit chaotic.

One nurse questions a patient who has had surgery for a retinal tear and who says she sees "black blobs from Mars." Yes, yes the blobs are bigger. No, no, I sleep with only one pillow and not two. Another nurse guides a patient over to an eye pressure machine and centers her pupil using a large monitor "Open, open," says the nurse, and then pulls a hidden switch that shoots a blast of air, making the large eye on the screen blink. A man in another room stares into a light box from a meter away and complains that he cannot read the letters on the card because the lighting is too flat. In another room a woman says that she sees holes in the light.

In the waiting room, a gentle retiree turns to his wife and says, "This 'golden age' is a lot of hooey." And a woman in a white hat, white dress, and a black patch over her left eye marches through the pre-lunch crowd to the information desk and slaps her tiny white purse down on the counter.

"I'm here to see Dr. Martin Friedlander," she says. "I have an 11 o'clock appointment. Now where do I sit?"

Laboratory Medicine

When Associate Professor Martin Friedlander dons his clinical hat every Wednesday, it is not to leave his cell biology laboratory bench behind for a few hours, but rather to bring his bench to that bedside. Once a week, Friedlander, who is a basic researcher and a medical doctor trained in ophthalmology with a subspecialty in retinal diseases, sees patients, the vast majority of whom suffer vision loss from diseases such as diabetic retinopathy and macular degeneration.

There are many causes of visual loss, but as a researcher and a clinician, Friedlander is primarily focussed on those resulting from neovascularization—the proliferation of new blood vessels under or on top of the retina, the "sensory" membrane that lines the eye, contains the rods and cones that capture photons, and signals the brain through the optic nerve.

Angiogenesis, the proliferation of new blood vessels, occurs in the eye most commonly in elderly patients (age-related macular degeneration) and in patients with diabetes (diabetic retinopathy). Most of Friedlander's patients who lose vision do so as a result of abnormal angiogenesis.

"As the population ages, one of the big problems will be quality-of-life issues, and eye diseases are significantly disabling," says Friedlander. "At the point in your life when you want to retire and play golf, bridge, or read, you may not be able to do these activities because you have macular degeneration or diabetic retinopathy."

Friedlander treats both of these conditions in his Wednesday clinics. The most commonly used current treatment is laser photocoagulation, which involves extensive destruction of retinal tissue with a highly focused argon beam, but Friedlander would like to have a less destructive, more effective, treatment.

He is a principle investigator on four clinical trials testing various anti-angiogenic compounds on patients threatened with vision loss because of diabetes or age-related macular degeneration. They are phase II (small efficacy and optimal dosage) trials in which patients of the clinic who meet the necessary criteria are recruited and given the treatment in a controlled fashion.

Friedlander's research in the laboratory, where he spends the bulk of his time, involves studying the mechanisms of angiogenesis and characterizing the pathways that underlie these mechanisms. Getting a handle on some essential molecule in the angiogenic pathways and making antagonists to those molecules might be useful in the treatment of neovascular eye disease.

"It turns out that [angiogenesis] has tremendous relevance to a broad range of blinding retinal diseases that we see in the clinic," says Friedlander. "Now we're going into the clinic to test whether advances in the laboratory can be translated into useful treatments for some of these diseases."

Friedlander's group uses corneal, retinal, and tumor models of angiogenesis—assays that have the advantages of being physiologically relevant, reproducible, fast, and simple. In the corneal models, selected molecules can be used to stimulate angiogenesis and a variety of antagonists can then be tested for efficacy in inhibiting new blood vessel growth. The retinal models are naturally occurring angiogenic ones and are not only useful for studying antagonists but also for gaining a better understanding of underlying, physiologically relevant mechanisms of angiogenesis.

With these basic assays, Friedlander's group has been characterizing and testing antibody, peptide, and organic antagonists to the Alpha-V Beta-3 and Alpha-V Beta-5 integrins. Integrins are heterodimeric cell surface proteins (denoted by their alpha and beta subunits) that mediate adhesion to other cells and to the extracellular matrix. Integrins are also important to the mechanism of angiogenesis. Blocking them in the eye could prevent neovascular blindness in certain cases.

In fact, cyclic peptide antagonists of these integrins developed by Merck KGaA, in collaboration with Friedlander and TSRI Professor David Cheresh, are already in clinical trials for treating certain cancers and should be in trials for ophthalmic diseases within the next one to two years.

Also in collaboration with the Cheresh group, Friedlander's group has defined two angiogenic pathways on the basis of the dependency of the pathways on these distinct Alpha–V integrins. "We also showed that antagonists specific to each of these integrins selectively inhibit one of these pathways and that such pathways are involved in human neovascular eye diseases," says Friedlander.

He recalls, "I had been interested in the potential of antiangiogenesis for treating eye diseases for many years. We knew that abnormal growth of new blood vessels played a major role in these blinding diseases. The problem was, we didn't have a rational approach to treating angiogenesis. At a dinner for new faculty, [TSRI President] Richard Lerner brought my attention to an upcoming journal article by David Cheresh on the integrin research. This research showed me that they knew something about the mechanism of angiogenesis, providing the basis for a rational therapeutic approach, something I had been looking for for years."

"One of the obvious benefits of being at an institution like TSRI is the quality of the collaborators and the multidisciplinary nature of the scientific environment," he continues. "This, plus the clinical relevance and general excitement of the research, makes it easier to attract an extraordinarily talented group of laboratory personnel from techs and admins to graduate students and post-doctoral fellows. These are the people that move the projects forward."

The two laboratories also study the role of the tumor suppressor genes p53 and p21 in these integrin-mediated angiogenic pathways and the antiangiogenic properties of the noncatalytic carboxy-terminal end of a matrix metalloproteinase enzyme called "PEX." PEX is a naturally occurring 29-kD protein that binds to and prevents localization of full-length, active matrix metalloproteinase-2 to the tip of proliferating new blood vessels. Recombinant forms of PEX inhibit angiogenesis in several laboratory models, which Friedlander has observed in vivo.

Recently, Friedlander's laboratory has initiated a collaboration with Skaggs Institute investigator Paul Schimmel to study the mechanism and clinical usefulness of fragments of tryptophanyl tRNA synthetases in inhibiting angiogenesis. "We are very excited about this project since it provides the opportunity to use gene- and cell-based therapies to deliver a molecule that, in our hands, is the most potent anti-angiogenic we have worked with to date," says Friedlander.

In the laboratory, he maintains a long-standing interest in studying the mechanism through which proteins are asymmetrically integrated into the cell membrane, a problem he initially became interested in while working in the laboratory of Nobel laureate Gunter Blobel at The Rockefeller University. "There are a number of inherited retinal degenerations that result in profound visual loss and have as their genetic basis mutations in integral membrane proteins such as rhodopsin and peripherin," says Friedlander. By studying the topogenic signals that serve to target, integrate and tanslocate these molecules into the cells of the eye he hopes to gain a better understanding of how the retina degenerates in diseases like retinitis pigmentosa and Leber's Congenital Amaurosis.

In collaboration with Immunology Associate Professor Glen Nemerow, Friedlander's group also has a program in Ocular Gene Therapy. Using modified adenoviral and cell-based delivery vectors, the goal of this program is to specifically target genes to different eye cell types in the treatment of inherited retinal degenerations and acquired neovascular diseases.

"While we have been learning much about the underlying gene defects in the inherited retinal degenerations and have identified potential therapeutic targets in neovascular diseases, we are still faced with significant challenges in effectively and efficiently delivering therapeutics to the posterior segment of the eye where these disease processes occur," says Friedlander. "Gene and cell-based delivery represent novel approaches to drug delivery that we are highly encouraged by."

From the Cornea to the Core

Applying basic science to clinically relevant problems in vision is something that Friedlander is involved with in an institute-wide fashion as well, as the principal investigator of the new Core Center for Vision Research at TSRI, which began operations on June 1 of this year.

Earlier this year, the National Eye Institute (NEI) announced multi-year funding for the core, which will support shared resources for 11 TSRI researchers who have independent programs in vision science funded through the NEI and six researchers from the University of California, San Diego (UCSD).

"Each investigator is an outstanding scientist in their own particular field," says Friedlander. "We found ourselves with a large group of individuals who all knew something about some small aspect of the visual system. It's precisely the sort of expertise that the NEI looks for in funding programs like ours."

A microarray core module will produce DNA "chip" microarrays that can be used for observing changes in gene expression during the course of normal and pathological changes in the eye. Similarly, a proteomics core module will provide global analysis of all the proteins expressed. A microscopy and imaging core module will allow the phenotypic state of eye tissue to be studied in conjunction with the expression data that comes from the microarray and proteomics cores.

Investigators using the microscopy and imaging core will be able to take advantage of new technologies in order to expand existing research, for example a state-of-the-art multiphoton scanning laser confocal microscope.

Friedlander hopes that the center will strengthen and expand existing basic research and facilitate professional interactions among TSRI investigators, UCSD scientists, and their clinical counterparts at Scripps Clinic and Scripps Memorial Hospital. "So that they become aware of potential applications of their research that may be related to diseases of the visual system," he says.

"The [core center] is not about curing a disease," he says, "but, rather, understanding the disease process and applying this fundamental knowledge to developing treatments for diseases that cause visual loss."

Back to the Clinic

Inside the doctor's office a woman has come from far away with a hole in her retina, complaining of white flashes and sore eyes. She worries that sometimes whole cars disappear. "[Can you] tell me," she says, "if I need more surgery?"

"Doctor—am I going blind?" she asks.

Friedlander looks into the back of her eye and says "no."


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TSRI Associate Professor Friedlander is a basic researcher and a medical doctor trained in ophthalmology. Photo by Alan McPhee

























"[The National Eye Institute core center at TSRI] is not about curing a disease, but, rather, understanding the disease process and applying this fundamental knowledge to developing treatments for diseases that cause visual loss."

Martin Friedlander














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