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The good news is that the number of researchers now working on macular degeneration is high enough to be in the
"critical mass" range, i.e the international research effort on macular degeneration is now on a scale which can be expected to yield steady and substantial progress in
understanding and treatment. The bad news is that, as usual at a large scientific meeting, almost all of the reports on macular degeneration were of preliminary exploratory work or of
incremental progress on continuing projects, rather than of breakthroughs. The abstracts of the reports are available from ARVO on a CD.
Putting Research in a Context: The Current Working Hypothesis on the events in AMD
Perhaps the greatest difficulty faced by a layman when reading research reports is interpreting the context in which the researchers made their
choices of projects and methods and gauging the interpretation and significance of their results. During the past couple of years, something we can call the Current Working
Hypothesis about the sequence of events in macular degeneration has emerged. It is the framework into which most of the research now being done on macular degeneration can be
fitted. The Current Working Hypothesis:
Vision begins with absorption of light quanta by a pigment-protein complex, rhodopsin, which is in the outer rim of disks stacked
in the light-sensing cells of the retina, the rods and cones. The pigment component of rhodopsin is derived from vitamin A (retinol). As a result of being used in a quantum-absorbing
event, the pigment molecule undergoes a structural change. It cannot function in another light-absorbing event until it has been rebuilt. The rebuilding or recycling process is
complex, involving disassembly of the photoreceptor outer segments, then export of the parts to cells of the Retinal Pigment Epithelium (RPE) for multi-step modifications, then return
of the rebuilt components to the rods and cones.
If the recycling process malfunctions, at any of a number of steps in the process, reactive intermediates accumulate and
by-products form. One or more of the accumulated molecules are toxic to rods, cones and/or RPE. Some of the accumulated intermediates occur in a deposit at the RPE called lipofuscin.
One component of lipofuscin is a dimeric derivative of retinol known by the acronym A2E. It is toxic to RPE, and is suspected of being a cause of damage and death of cells in the
retina. The damage and death shows up as abnormal pigmentation and scarring of the retina. If enough of it occurs, central vision deteriorates as the dry (i.e. geographic
atrophy) form of AMD develops.
Another material which accumulates at the RPE when the recycling process functions suboptimally is drusen. In additions to lipides, it
contains protein components of the immune system. Available evidence indicates that, in contrast to lipofuscin, drusen is not in the causal chain of events of macular degeneration.
Behind the RPE is Bruch's membrane, which separates the retina from the choroid, which contains the blood vessels that service the retina. If RPE is sufficiently damaged, Bruch's
membrane can lose its integrity. Cellular growth factor proteins of the VEGF type (Vascular Endothelial Growth Factor) are produced by RPE, and normally are prevented by Bruch's
membrane from reaching the walls of the blood vessels in the choroid. Loss of integrity of Bruch's membrane, plus activation of VEGF receptors in the walls of vascular cells can
result in the initiation of neovascularization. If the resulting new blood vessels leak into the retina, the condition is called neovascular, or wet, AMD. VEGF receptors, which are
cell membrane-bound proteins, are activated by phosphoylation of a tyrosine residue, a reaction catalyzed by an enzyme in the protein kinase family. Thus the initiation of
neovascularization in late-stage AMD is currently thought to result from loss of integrity of Bruch's membrane, and movement of VEGF across Bruch's membrane from RPE to activated VEGF
receptors in the walls of blood vessels in the choroid.
An alternative hypothesis some researchers still persist in exploring, namely, that neovascularization is part of an
orderly compensatory response to reduced blood flow in the choroid vessels, does not appear to be correct.
Age Related Maculopathy (ARM) is the term used for a
clinically diagnosable pre-condition which leads to Age Related Macular Degeneration (AMD) in some individuals. ARM is characterized by:
- drusen on the macular part of the retina
- abnormal pigmentation in the macula
- scarring of the macula
- little or no detectable decline of visual acuity
ARM may be thought of as the clinical manifestation of a moderate malfunctioning of some step in the recycling
process. People with the symptoms of ARM who in addition have detectable loss of visual acuity are said to have dry AMD. ARM patients with large and numerous drusen are the most
likely to develop AMD.
Research Targets
Numerous reports at ARVO 2002 explored the research targets suggested by the Current Working Hypothesis. Those described below may ultimately provide the basis of developing a
treatment for macular degeneration.
Protein kinase inhibitors.
A particularly popular approach is to try to block activation of the neovascularization process at the protein kinase reaction step. For years, drug companies and academic researchers have been developing low molecular weight, synthetic chemicals which have protein kinase inhibitor activity, because of the importance of various protein kinases in regulating many cellular processes. Researchers are trying to take advantage of this knowledge base to develop protein kinase inhibitors which will favorably affect neovascular AMD. So far, no clear winner has yet emerged.
Angiogenesis inhibitors.
The process called neovascularization in retinal diseases is called angiogenesis in other situations in the body, notably growth of solid tumors. Researchers have been hunting for regulatory proteins with angiogenesis inhibitor activity for years, in the hope that they might be useful as anticancer drugs. Researchers have been testing such angiogenesis inhibitors as possible drugs to treat neovascular AMD. The use of such proteins as drugs has two large disadvantages relative to low molecular weight synthetic compounds: 1) they are much more difficult and expensive to produce, and 2) they tend to be much less stable, especially after administration.
Metalloproteinase modulators. There is
a family of enzymes called metalloproteinases which break down proteins which exist in and make up, the extracellular matrix, i.e. the space between cells. There are naturally
occurring proteins which inhibit certain of these metalloproteinases. One of the juvenile, i.e. genetic, types of macular degeneration, is caused by mutations in a metalloproteinase
inhibitor gene. There is evidence that the effect is on the extracellular matrix in the vicintiy of the RPE. This has prompted some researchers to hunt for compounds which will
inhibit or activate metalloproteinases and study the impact of modulating metalloproteinases on macular degeneration. Again, no clearly successful therapeutic application of
modulation of metalloproteinases for treatment of macular degeneration has yet emerged.
A2E modulation.
Because A2E has been shown to be toxic to RPE, some researchers are studying the mechanism of that toxicity, and hope to find ways to minimize either the formation of A2E or its toxic impact.
Culturing and transplantation of RPE. Because rods and cones are "hard-wired", i.e. connected to the optic nerve and the brain via neurons in the retina, replacing
damaged rods and cones will necessitate correctly "wiring" them, which is a rather daunting objective. RPE cells on the other hand, are not connected to neurons, multiply in
culture, and repopulate zones cleared of RPE when transplanted into them in damaged retinas. Researchers are trying to develop ways to replace damaged RPE with healthy RPE. The major
obstacle appears to be graft rejection when the transplant is not genetically matched to the recipient.
Noteworthy News
How Many People Have Age Related Macular Degeneration?
No part of the U.S. Government, not the National Eye Institute, not the Center for Disease Control, not the Census Bureau, has a program for
measuring and monitoring the prevalence (i.e. the frequency in the population) of Age-related Macular Degeneration (AMD) or the pre-condition known as Age-related Maculopathy (ARM).
Consequently, estimates of prevalence are made by extrapolating from independent studies of groups, each group typically consisting of a few thousand individuals. A major complication
in combining data from independent studies is that the classification criteria are typically unique for each study.
A group at the Willmer Eye Insitute of the Johns Hopkins
University (Friedman et al., ARVO 2002) pooled and reconciled data from 8 studies into a metastudy, in order to come up with estimates of the prevalence of AMD and ARM in the U.S.
population. Applying the estimate of prevalence to US Census figures, they estimated that 1.65 million people in the U.S. have either geographic atrophy (i.e. dry AMD) or neovascular
(i.e. wet) AMD. They also estimated that 5.6 million people in the US have large drusen (a symptom of ARM), which is the strongest predictor of future development of AMD.
A separate estimate of people of European descent who are blind in one eye from AMD suggests that 20% of people of European descent with AMD are blind in one eye.
Perhaps the
most surprising result of this metastudy was that about 57% of people with AMD are estimated to have the neovascular type. Conventional wisdom has been that only about 10 - 20%
of AMD cases are neovascular. The origin of this discrepancy remains to be determined.
The above prevalence estimates for the US population - 1.65 million with AMD, 5.6
million with ARM - are probably the best available estimates.
Byproducts of the AREDS Study
Almost a decade ago, the National Eye Institute agreed to fund a multi-site Age Related Eye Disease Study (AREDS), to
determine if supplements containing certain vitamins and zinc had an impact on the development of AMD. Back then, some researchers thought that perhaps vitamins C and E,
beta carotene, and perhaps zinc, might reduce the risk of developing AMD. AREDS groups started taking a vitamin cocktail with and without zinc, or zinc alone, and were monitored for
the next five years.
People who had large drusen but no AMD at the beginning of the study were the most at risk for developing AMD, about 16% in 5 years. Those with large
drusen who took either the vitamin cocktail alone, or with zinc, had a 25% lower probability of developing AMD during those 5 years, i.e. about 12% in 5 years. People with small
drusen had a much lower probability of developing AMD within 5 years, 4 - 5%, regardless whether or not they took the vitamins or zinc.
AREDS was begun before the
recognition of the carotenoids lutein and zeaxanthin as the macular pigments, and of the possibility that declining macular pigment density might be a causal factor in AMD.
Consequently, lutein was not included in the AREDS protocol. So far there is evidence that macular pigment declines slightly with age, and slightly more so in people with AMD, but
there is no evidence that the decline is causally related to AMD. Also, there is no experimental evidence showing that vitamin and/or zinc supplements are of benefit to people who
already have AMD. Nevertheless, diet supplements containing the AREDS cocktail plus lutein are now in wide use by people with AMD, often on the advice of their
ophthalmologists.
One researcher studying macular pigment commented that it was now very difficult to show a decline in macular pigment with AMD because so many people with AMD
are taking a diet supplement with lutein. We are thus in the midst of a large uncontrolled experiment, in which people with AMD have raised their macular pigment density. It is to be
hoped that some day we will learn of the consequences, and that they will not be undesireable ones.
Cholesterol is not a predictor of AMD
There has been speculation for years that perhaps AMD is caused by poor
circulation in the blood vessels behind the retina, which nourish and oxygenate the cells of the retina and remove wastes, i.e that AMD has a cause similar to heart disease.
Consistent with this idea are the facts that high blood pressure increases risk of developing AMD, and blood flow behind the retina has been shown to decline slightly with age and
slightly more in people of the same age with AMD. However, there has been no direct evidence that AMD is caused by poor circulation behind the retina.
High serum cholesterol is
a well established risk factor for heart disease. It was therefore of interest to know if there is a similar relationship between serum cholesterol and AMD. The serum cholesterol
levels were monitored in people in the AREDS. High serum cholesterol was not a statistically significant predictor of which people in the AREDS would develop AMD. (Seddon et al, ARVO
2002).
A Large Racial Difference
AREDS turned up a striking racial difference. Although the probability of developing AMD in 5 years in people with large
drusen is similar for whites and blacks at age 65, a very large difference is evident at age 80. Whites with large drusen and in their 80s are 4 times more likely to develop AMD than
are blacks. We can expect researchers to study this population difference closely. With luck they might find a clue as to the cause of the greatly increased risk in whites over
80.
New Treatment for Subfoveal Neovascular AMD with recovery of Visual Acuity
The fovea is a very small part of the retina at the very center of the macula. It has a very high concentration of cones, and plays a
disproportionately large role in our ability to see detail and color. Neovascularizations behind the fovea can severely damage central vision. Until the development of
photodynamic therapy (PDT), there was no FDA-approved treatment for subfoveal neovascularizations. However, PDT is suitable for classical neovascularizations, but not occult ones.
Furthermore, PDT only benefits about 1 in 5 of people treated. Also, PDT requires multiple treatments, and at best only slows the progress of the disease. Thus there is ample
room for development of more effective treatments.
An Austrian team (Binder et al, ARVO 2002) reported combining surgical removal of subfoveal neovascularizations with
transplantation of healthy RPE cells from the near-nasal region of the same eye, into the foveal region with the damaged RPE. They reported that more than 50% of treated eyes gained
at least two lines of visual acuity, and almost all the rest had no loss of visual acuity. In addition to the subjective evidence (visual acuity), objective evidence of repair of the
damage to foveal function was obtained in multifocal electroretinograms (MF-ERGs). The central peak signal in MF-ERGs of treated eyes was elevated compared to pre-operative MF-ERGs.
This is perhaps the most positive outcome reported for any experimental treatment of any form of AMD. Providing that other surgical teams can learn to perform this procedure, we can
expect it to be evalutated by other centers in the coming year.
First Animal Model of AMD
An Australian team (Rokoczy et al, ARVO 2002) has developed a genetically engineered mouse which develops an AMD-like condition
in old age. They set out to create a mutant gene which would interfere with the recycling of photoreceptor outer segments, in the hope of causing accumulation of recycling
intermediates and side products. The gene targeted was cathepsin D, a proteolytic enzyme in lysosomes, which may be thought of as the garbage disposal organelles of cells. The
alteration of its amino acid sequence prevented an activating cleavage of the pro-protein. This strategy indeed caused gradually increasing accumulation of drusen-like debris at the
RPE and morphological changes in the RPE, over 18 months.
While abnormal functioning of cathepsin D is not known to be a factor in macular degeneration, any disturbance of the
recycling of photoreceptor outer segments has the potential to cause macular degeneraton, if the Current Working Hypothesis is correct. The resemblance of the retinal pathology in
these trangenic mice to human AMD was predicted by, and is therefore supportive of, that hypothesis. Investigations of the effects of the accumulating debris, and of ways to
minimize the harmful effects, can be expected to be done on this model system. |
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