La Jolla, CA (10/21/99)- New anti-angiogenesis compounds appear promising
as treatments for previously untreatable eye diseases, reported Martin
Friedlander, MD, Ph.D., a researcher at the Scripps Research Institute, who
spoke at a recent seminar of the Research to Prevent Blindness Foundation.
Angiogenesis is the growth of new blood vessels from preexisting
capillaries. Normally this process only occurs in humans during embryonic
development, menstruation and as part of wound healing. However, a number
of diseases particularly cancer and a number of blinding eye diseases involve
unwanted angiogenesis. In the case of cancer the new vessels feed the tumor
and allow it to grow. In the case of eye disease, new vessels grow behind
or in front of the retina, impairing vision.
Age-related
macular degeneration (ARMD) and diabetic retinopathy are the leading causes
of blindness in people over the ages of 65 and under 65 respectively. Both
of these blinding eye diseases are characterized by the growth of abnormal
blood vessel growth in the retina. As the new vessels grow they interfere
with the transmission of light to the back of the eye, impeding vision.
"The proliferation of new blood vessels is a common feature
in many ocular diseases including not only age-related macular degeneration
and proliferative diabetic retinopathy but also rubeotic glaucoma, interstitial
keratitis and retinopathy of prematurity. It is also a leading factor contributing
to corneal graft failure. If we can selectively target new vessels involved
in the disease processes, while leaving old vessels alone, then we would have
a way to shut down these angiogenic processes," said Dr. Friedlander.
The growth of new blood vessels is also a feature in the spread of many
forms of cancer. In fact, clinical research in the cancer
field has paved the way for the new treatment approaches for eye disease.
Several anti-angiogenic compounds are now in clinical trials for the treatment
of cancer, including vascular endothelial growth factor (VEGF) and fibroblast
growth factor (FGF). Preliminary results suggest that these factors are able
to slow or stop the growth of the blood vessels tumors depend upon to survive
and grow.
Clinical studies with anti-VEGF antibodies and other VEGF-blocking
molecules are now underway to evaluate the potential of this approach for
treatment of diabetic retinopathy and ARMD. There is
more to the story than VEGF. Working with noted angiogenesis researcher Dr.
David Cheresh, Dr. Friedlander is evaluating another aspect of angiogenesis
involving a class of molecules called integrins. One particular integrin,
alpha-V-beta-3, is known to be activated on newly sprouting blood vessels.
Dr. Friedlander and colleagues have been able to create molecules to block
alpha-V-beta-3 and shut down tumor growth.
"I had been interested in 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. Dr. Cheresh's work on integrins
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 years," Dr. Friedlander said.
Dr. Friedlander's focus is on integrins how interact with
VEGF and FGF-driven angiogenesis processes. In his early work, Dr. Friedlander
confirmed that the alpha-V-beta-3 integrin was indeed expressed on
new vessels growing in the eye. He also found that he could shut down this
process by using an antibody antagonist developed in the Cheresh lab, shut
down new vessel growth in animal eye models.
Subsequent research revealed that different integrins were
activated depending on where in the eye the new vessels are growing. In some
cases VEGF was involved, while in other cases FGF was a more important factor.
The researchers showed that patients with ARMD, who have new vessels growing
under the retina, expressed mostly alpha-V-beta-3 Patients with diabetic retinopathy,
in contrast, activated two integrins, alpha-V-beta-3 and alpha-V-beta-5.This
knowledge has important implications for understanding
both the cause of these diseases and potential treatment approaches. .
Clinical studies of the effects of integrin-blocking compounds in patients
with ARMD and diabetic retinopathy are in the early stages. .
Matrix metalloproteinases (MMPs) are enzymes involved in regulating
the extracellular matrix, the cellular superstructure that holds our bodies
together. They are involved in many cellular processes including angiogenesis.
Dr. Friedlander's lab is looking for a way to block MMPs involved in angiogenesis
selectively, without interfering with other vital processes. The
researchers may have found a more selective MMP. Recent research showed that
actively growing matrix cells have a way of localizing a specific MMP, called
MMP2, to the tips of new vessels. The research showed that MMP2 can degrade
into another molecule called PEX (carboxy-terminal non-catalytic domain).
PEX in turn can bind to the alpha-V-beta-3 integrin, offering another
way to shut down angiogenesis.
A number of older medications not originally intended for treatment of eye
disease also show promise in this field. For example, researchers
have known for many years that the class of drugs known as corticosteroids
have antiangiogenic properties. However, the severe side effects that accompany
long-term use of these drugs have precluded their use in eye disease. A new
potent angiostatic steroid, anecortave acetate, that is free of the glucocorticoid
component that causes these side effects, may be the answer. Clinical studies
of this agent are now in the advanced stage and appear promising. .
Dr. Friedlander is also conducting a study of another drug
that was not originally developed for treatment of eye disease, called somatostatin.
It may have never entered clinical trials had someone not observed many years
ago that diabetic dwarves had a far lower incidence of diabetic retinopathy
than normal adults did. It was also observed some years ago that some women
who developed a condition after pregnancy in which the pituitary gland ceased
to function often had resolution of severe diabetic retinopathy. A worldwide
trial with somatostatin for treatment of diabetic retinopathy is now underway.
Cell based delivery is another option his lab is exploring.
As director of the Ocular Gene Therapy Program at Scripps he oversees research
involving ways to incorporate useful compounds directly into the cells involved.
One approach involves using genetic engineering to introduce a gene into cells
that will then produce a protein or peptide. Another approach they are looking
at involves putting genetically engineered cells into a semipermeable membrane,
and putting that membrane inside an inert container. This type of implant
would allow slow release of a medicine or protein without fear of triggering
an immune response. Still another approach involves using the outer coating
of the eyeball, known as the sclera, as a kind of sponge. It may be possible
to inject the sclera with a therapeutic compound and then let that compound
seep into the eye over time.
FACTS AND FIGURES
ARMD is the leading cause of blindness in Americans over 65
years old. The disease affects as many as 15 million
Americans over the age of 65, of which 15% are expected to
experience vision loss as a result of new vessel growth in the eye. The number
of cases of ARMD is expected to triple in incidence
in the next 20 years, as the population ages. There is currently no
cure or effective treatment
Diabetes retinopathy is leading cause
of blindness in Americans less than 65 years of age.
There are 16 million diabetics in US of whom 40,000 per year develop ocular
complications. There is also no effective cure or treatment for that disease,
although laser treatment may slow the progression of the disease.
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