O How to keep photoreceptors alive

How to keep photoreceptors alive
Alan Bird*
Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom
ver the last 40 years, there
has been increasing success in
the surgical treatment of retinal detachment in that the
retinal reattachment could be achieved
in a high proportion of cases but visual
recovery was frequently poor. An explanation for this poor visual outcome was
derived from work on experimental retinal detachment in which it was shown
that photoreceptor cell death occurred
because of a wave of apoptosis during
the first few days of retinal detachment
(1). It is recognized that apoptosis or
programmed cell death is a genetically
encoded potential of all cells (2). It is
characterized by cleavage of most of the
nuclear DNA into short but well organized chains of nucleosomes in multiples
of 200 bp by an endogenous nonlysosomal nuclease (3, 4) and may be triggered by changes in the metabolic environment of the cell. The photoreceptor
cells are closely approximated to the
retinal pigment epithelium (Fig. 1) and
depend on the retinal pigment epithelium for their metabolic sustenance.
Physical separation of the two and loss
of metabolic exchange as occurs in retinal detachment (Fig. 2) might have been
supposed to cause a sequence of events
that would inevitably induce cell loss
that was not amenable to treatment.
However, apoptosis may be manipulated
by altering the metabolic environment,
and it has been shown that brainderived growth factor injected into the
eye reduces the rate of photoreceptor
cell loss in experimental retinal detachment (5), although the precise means by
which apoptosis was induced and the
mechanism of the therapeutic effect
were uncertain.
In this issue of PNAS, Nakazawa et
al. (6) describe convincing evidence that
monocyte chemoattractant protein 1
(MCP-1) plays a critical role in inducing
photoreceptor apoptosis in experimental
retinal detachment in mice. It had been
reported some years ago that levels of
MCP-1 were high in the vitreous of patients with retinal detachment (7).
MCP-1 seemed to be an attractive candidate as an inducer of cell loss because
it had been proposed as playing a role
in the pathogenesis of a variety of disorders of the central nervous system including Alzheimer’s disease. Nakazawa
et al. showed that the level of MCP-1 in
mice with retinal detachment was increased 10-fold in the vitreous when
compared with normals and that its ex-
Fig. 1. Photomicrograph showing the close physical relationship between the photoreceptor cells
of the retina and the retinal pigment epithelium
(RPE). There is constant metabolic exchange between the two cell systems. (Magnification:
pression in Muller cells (a class of retinal glial cell) was up-regulated after
72 h of detachment, a time of maximum
apoptosis. Apoptosis was reduced by
injecting an anti-MCP-1 blocking fragment intravitreally. Apoptosis was also
reduced by 80% in MCP-1 knockout
mice with retinal detachment. In each
case, suppression of apoptosis was accompanied by reduction of CD11b⫹
macrophage/microglial cells, invading
cells that are found universally in retinal
detachment. Interestingly, Nakazawa et
al. provide evidence with both in vitro
and in vivo experiments that the effect
is not mediated by a direct effect of
MCP-1 on photoreceptor cells; rather, it
was mediated through the activated
macrophage/microglial cells. This information is very important because there
are clear therapeutic implications for
the acute management of retinal detachment in humans. Hopefully it will be
possible to transfer these findings into
treatment strategies that can suppress the
photoreceptor cell loss such patients often
These findings also have broad implications for retinal diseases, including
diabetic retinopathy, retinal vascular occlusions, and retinal dystrophies. A brief
summary of relevant work on the pathophysiology of retinal dystrophies and
experimental therapeutics for these dystrophies will serve to put the work of
Nakazawa et al. (6) in perspective. In
both humans and animals, there has
been increasing reason to believe that in
Fig. 2. Diagram of a cross-section of the eye with
retinal detachment (open arrow) and retina hole
(solid arrow). Fluid exchange between the subretinal space and vitreous cavity through the hole
compromises metabolic exchange between the retina and retinal pigment epithelium.
inherited retinal diseases, the metabolic
defect caused by the mutation does not
cause cell death directly. This observation is evident clinically with respect to
cone loss in patients with retinitis pigmentosa caused by mutations in the
rhodopsin gene, which is expressed exclusively in rod photoreceptor cells. A
similar situation exists in mice transfected with a mutant rhodopsin gene (8,
9). It is also illustrated in the setter dog
with progressive atrophy of both the rod
and cone photoreceptors, with phosphodiesterase activity being defective in
rods but not in cones (10). Most striking
are the observations on a chimera created of a pigmented mouse transfected
with a mutant rhodopsin gene and a
WT albino mouse. The setting was
achieved by generating chimeric embryos composed of cells from both the
albino and pigmented mouse lines. Although there was patchy distribution of
cells from the pigmented and nonpigmented origin, the distribution of photoreceptor cell death followed exactly the
same pattern as that seen in the pigmented rhodopsin mouse, implying that
Author contributions: A.B. wrote the paper.
The author declares no conflict of interest.
See companion article on page 2425.
*E-mail: [email protected]
© 2007 by The National Academy of Sciences of the USA
PNAS 兩 February 13, 2007 兩 vol. 104 兩 no. 7 兩 2033–2034
the cells containing the mutant gene
were no more likely to die than the cells
with the WT rhodopsin gene. The only
recorded variation between animals was
that the proportions of mutant to WT
populations determined the speed of
degeneration. It was concluded that the
disease was induced by the presence of
the mutant photoreceptor cells, but cell
death was somehow related to a change
in the environment of the retina rather
than a direct and cell-autonomous effect
of the mutant gene.
These observations stimulated further
investigations of the cause of cell death
in retinal dystrophies, and it became
evident that cell loss is universally
caused by apoptosis (11–13). This finding gave rise to the concept that modulating the risk of apoptosis by using
growth factors may have therapeutic
value. The first attempts were in Royal
College of Surgeons rats in which the
causative gene is expressed in the retinal
pigment epithelium but causes death of
photoreceptor cells. A single intravitreal
injection of basic fibroblast growth factor caused prolongation of photoreceptor cell life (14). A series of trials were
then undertaken in a light damage
model (15) and genetically determined
disease in rodents (16) using a variety of
growth factors given as single intravitreal injections. These experiments
showed variable rescue of photoreceptor
cells depending on the neurokine used
and the disease model and mode of delivery. Ciliary neutrophic factor (CNF)
appeared to be consistently effective in
a variety of models in rodent, cat, and
dog. However, the rescue was inevitably
short-lived given the limited exposure of
the retina to the growth factor. With the
advent of successful gene transfer into
the retina (17, 18), it was possible to
generate long-term treatment. A recombinant adeno-associated virus was used
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after single injections into the subretinal
compartment. However, there were unexpected side effects that appeared to
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patients with severe retinitis pigmentosa
by using a slow-release biological device
consisting of cells transfected with the
human CNF gene and sequestered
within capsules that were surgically implanted into the vitreous cavity of the
eye (20). As a safety trial, it was successful in showing no untoward effect.
The severity of visual loss and the small
number of subjects involved was believed to preclude any conclusions as to
efficacy, but, surprisingly, some improvement in vision was recorded. Of
seven eyes for which visual acuity could
be tracked by conventional reading
charts, three eyes reached and maintained improved acuities of 10–15 letters, equivalent to a two- to three-line
improvement on standard Snellen acuity
charts. These results are very encouraging because the primary objective was to
slow degeneration rather than cause improvement in vision. Whether visual
gain is a realistic objective will need to
be tested in a phase II trial.
For the clinician managing patients
with retinal diseases, there have been
only limited opportunities to influence
the natural history of common diseases,
and in disorders such as retinal detachment in which surgical treatment was
available, the results with respect to visual recovery have frequently been disappointing. Similarly, laser treatment of
diabetic retinopathy inevitably involves
substantial retinal destruction to achieve
therapeutic benefit that was often timelimited. We are now entering an era of
biological treatment, including gene
therapy and the manipulation of disease
with neurokines, that is based on a better knowledge of pathologic mechanisms. The work of Nakazawa et al. (6)
presents the potential for significant
clinical applications by pointing to a
novel therapeutic target. Limiting the
retina’s exposure to MCP-1 could be
beneficial in the context of many retinal
disorders. With respect to inherited retinal dystrophies, this approach stands in
contrast to gene-therapy approaches in
which a separate genetic construct is
likely be necessary for each disorder.
After years of limited therapeutic opportunities, there are now a number of
promising new approaches derived from
experimental work, and it is likely that
cooperative work between laboratory
scientists and clinicians will transform
treatment of retinal diseases over the
next decade. The importance of these
advances cannot be overemphasized because retinal diseases account for ⬎70%
of severe vision loss in the Western
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to deliver minigenes that code for a secreted form of CNF under control of a
chick ␤-actin promoter (19). Long-term,
panretinal rescue of photoreceptors, as
protein-1 plays
a critical role
in inducing
2034 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0611014104