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."
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