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MACULAR DEGENERATION
Clinical
As a prototype for the rest of the brain, the retina has
long been an attractive tissue to study. It is accessible,
has a readily apparent organisation and there are many
tools available to aid analysis. However, the retina is
not only a good model for physiology and pathology in other
parts of the nervous system, it is also important clinically
in its own right.
Retinal degenerations are the commonest
cause of blindness in the Western world where over 1 in
20 of the population
will develop RD at some stage in their lives. Clinically
they are divided into two major groups, the retinitis pigmentosas,
in which the brunt of the pathology is initially born by
the peripheral rods and the macular degenerations in which
the brunt of the pathology is initially born by the central
cones. Retinitis pigmentosa (RP) is estimated to affect
1 in 10,000 people and age-related macular degeneration
(AMD) 15 million people (Fine
et al., 2000). Within these
broad categories lie over 120 differently mapped conditions
involving the retina (see Retinal
Information Network).
The causative gene has been identified for approximately
one third of these conditions, but remains elusive for
the majority. More importantly, even in those diseases
for which the gene is known, the pathway of degeneration
remains poorly understood.
Age-related macular degeneration
The commonest cause of macular degeneration, and indeed
of blindness in the western world, is age-related macular
degeneration (AMD), and thus deserves particular attention.
Moreover, there is evidence that the incidence may be increasing
at a rate higher than would be expected on the basis of
aging alone (Evans
and Wormald, 1996; Evans
et al., 2002).
Although the clinical hallmark of AMD is a loss of central
vision, the ophthalmoscopic appearance varies greatly from
patient to patient. A common feature is loss of retinal
pigment epithelium (RPE) cells, giving an irregularly pigmented
appearance on fundoscopy. The condition is divided into
the wet (20%) and dry (80%) forms. In wet macular degeneration,
new blood vessels grow from the choroid into or just beneath
the retina. They grow through Bruch's membrane, a thin
sheet of extracellular proteins and polysaccharides separating
the choroidal blood vessels and the RPE. This neovascularization
is prone to bleeding and subsequent scarring. The underlying
cause of the cell death could be intrinsic RPE pathology,
or secondary to photoreceptor pathology, given the intricate
physiological relationship RPE cells have with the adjacent
photoreceptors.
Source: National Eye Institute, National
Institutes of Health
AMD is multifactorial, but is believed to have a genetic
component. Indeed, one of the main problems in studying
AMD is that it may encompass several distinct conditions.
Disease progression, age of onset and phenotypic appearance
vary considerably from patient to patient. Candidate gene
studies, using genes identified in hereditary macular degenerations
with a similar phenotype, have suggested, but not yet conclusively
identified, susceptibility genes.
The problems of genotype-phenotype correlation One of the problems of trying to model retinal degenerations
by replication of single gene mutations in animals is the
often poor correlation between genotype and phenotype in
humans. For example, numerous clinically different retinal
disorders can be caused by single mutations in either rhodopsin,
peripherin or ABCA4. Whilst attempts are made to correlate
particular phenotypes with mutations in particular parts
of the underlying genes, this fails to provide a complete
explanation, highlighted by the original family carrying
P23H rhodopsin mutations. The propositus, a 49 year old
woman, was blind from loss of both cone and rod photoreceptor
function. In contrast, her older sister, who also had no
rod function, was able to drive a truck at night as her
occupation, such was the level of her surviving cone function
(Sun
and Nathans, 2001). Why did her sister's cones die,
since they did not express rhodopsin? Contradistinctally,
what genes in the sighted sister kept her cones alive ?
A further example comes from a man harbouring a T17M rhodopsin
mutation in which the top half of his retina survived,
whereas the lower half degenerated, such that he lost all
cones, rendering him severely disabled (Sun
and Nathans, 2001). Yet he could see objects below the equator. If
the T17M mutation is lethal to rods, why did the superior
rods not die? Was there an additional factor in the inferior
retina which led those rods to die, or an additional factor
in the superior retina which was responsible for the survival
of those rods ? Although the identification of these as
yet unidentified factors may be difficult, the encouraging
point is that they offer strategies for preventing degeneration
of photoreceptors harbouring otherwise lethal mutations
(Papermaster,
1995).
A further major problem is the lack of good models of
macular degeneration. Rodents are nocturnal animals with
poor color vision. They have a rod dominant retina, with
cones only making up 7% of photoreceptor number. In contrast,
cone degenerations make up the majority of the human retinal
degenerations, with AMD accounting for the majority of
cases of blindness in the Western world. Indeed, the CPFL-1
mouse identified in the Jackson screen was the first naturally-arising
mutation to cause cone function loss in the mouse. The
mutant has a complete loss of cone function from birth,
with a later loss of cone number (Chang
et al., 2002).
It may, therefore, serve as a model for congenital achromatopsia
in humans, but its value in studying macular degeneration
is less clear.
Treatments
There is a dearth of treatments in development for macular
degeneration. Most are focused on treating angiogenesis.
This is a complication of the rarer, wet form of macular
degeneration. Even if the new blood vessel is successfully
treated, the underlying retinal degeneration progresses
at the same rate.
DL approach
DL focus is on treating the underlying disease state.
Our approach is to identify therapies which will be applicable
across all subtypes of disease and will promote survival
of the photoreceptors, rather than just treat complications.
 .
Section of human (left) and
zebrafish (right) retina
A major component of the DL approach is the use of an
experimental system rich in cones, amenable to sophisticated
screening. The zebrafish retina resembles closely the human
retina, both exhibiting a similar cell layout (figure above).
Importantly, zebrafish have rich colour vision, with a
corresponding cone dense retina, an important advantage
over the rodent models. Indeed, the evolution of rodents
to a nocturnally-tuned retina is reflected genetically.
For example, the retinal guanylate cyclase-activating proteins
GCAP1 and 2 are expressed in human rod and cone photoreceptors,
with GCAP3 expressed solely in cones. In contrast GCAP3
is not expressed in the mouse retina. However, as in the
human retina, GCAP3 is found in the zebrafish cones (Imanishi
et al., 2002).
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