made a commitment to the Inherited Retinal Disease Register
of $118,500 for a further year to April 2014, with RA(NSW)
pledging $38,200 of this amount
also granted Associate Professor Erica Fletcher.
$40,000 for continuation of her work in 2013.
received funding from the NH & MRC in the 2012 round and is
very strong. The project examines the role of gliosis in the
degenerating retina, using a novel mouse model. Gliosis
onsets in the retina in the later stages of retinal
degeneration, and impacts on inner retinal function.
If people with
long term retinal dystrophies are to benefit from newly
engineered bionic devices, then gliosis needs to be managed
and if possible reversed.
Professor Fletcher's lay description of the work follows.
The role of gliosis in advanced retinal degeneration
Development of treatments that provide novel ways of
replacing photoreceptors assumes that the neurons that make
up the inner retina remain intact, and that are cells
capable of passing any light signals to the brain. However,
there is a great deal of evidence from animal models of
retinal degeneration and humans cases of Retinitis
Pigmentosa that the inner retina undergoes a series of
extreme changes. We have developed a novel transgenic mouse
that allows us to detect functional changes in the inner
retina well after animals are completely blind. Our data
shows that retinal ganglion cells, the output neurons of the
retina, undego a series of changes well after the loss of
photoreceptors, and that ganglion cells become dysfunctional
and die because of changes in support cells within the
retina called glia. In this project we will first examine
the functional and morphological changes in retinal ganglion
cells in two transgenic models of retinal degeneration.
Secondly, we will examine how changes in the support cells
(glial cells) affect ganglion cells and finally, we will
evaluate whether presentation of glial proliferation
ameliorates the inner retinal plastic changes and in
particular preserves ganglion cell number and function.
information generated from this project is crucial for the
optimal development of technologies like electronic retinal
AUSTRALIAN INHERITED RETINAL DISEASE REGISTER AND DATA BANK
With the support of its State bodies, Retina
Australia is providing funds to expand the Inherited Retinal
Disease Register and DNA Bank held in Western Australia at
the Sir Charles Gairdner Hospital, to include all persons
within Australia with an inherited retinal eye disease, and
selected blood relatives who wish to participate.
The procedure is simple - a sample of blood
or saliva is taken, and forwarded to the IRDR laboratory
where the DNA is extracted and held in secure conditions.
This material will form a databank of samples
which will be made available to any gene therapy researcher
in the world who seeks to make use of it. In the
future, when funds are available, the DNA material will be
‘sequenced’ to ascertain the individual’s specific errant
retinal gene, or in the case of blood relatives, whether or
not they carry the gene.
For people living in NSW, information about
participation in the Inherited Retinal Disease Register can
be obtained by contacting Retina Australia (NSW).
Intensive research has been fostered by
the world’s RP groups and is making headway in unravelling
the mysteries of RP and will hopefully soon lead to
effective treatment and ultimately a cure.
Current approaches to research
- Understanding the structure and
function of the retinal cells and their interaction with
connections to the brain.
- Modification of the diseased
retinal cells by genetic manipulation.
- Replacement of the diseased
retinal cells with stem cells - derived either from
embryos or adults.
- Insertion of electronic equipment
to function as a bionic eye.
valuable research in Australia is contributing to the global
effort in trying to overcome RP and other degenerative eye
diseases. Australian research is funded by Retina Australia,
through its grants program, and the National Health and
Medical Research Council (NH&MRC).
The Board of Retina Australia
has made grants totalling $139,700 to four research projects
being undertaken at Australian universities during 2011.
This amount has been possible due to the extremely hard work
done by state RP organizations in raising funds for
research, and to the generous supporters who continually
respond to their fundraising efforts.
A further grant was awarded
to Dr Erica Fletcher, University of Melbourne
whose continuing research is
encouraging. She explains:
currently funded NHMRC grant is aimed at examining in detail
how the molecule, ATP, causes photoreceptor death, and
whether blockade of this class of molecule slows
photoreceptor death in two animal models of retinal
degeneration. We propose that in those with RP or animal
models, death of rods causes the release of large amounts of
ATP which subsequently causes death of neighbouring rods and
“What we have achieved so far:
We have made considerable progress in understanding the
mechanism and time course by which ATP kills photoreceptors.
In addition we have found that compounds that block the
action of ATP slow photoreceptors down in animal models of
retinal degeneration, and that photoreceptor loss is reduced
in an animal that lacks expression of receptors for ATP.
“What we plan to do in 2011:
For 2011, we will be
expanding this work, and in particular will be concentrating
on the mechanism by which ATP affects photoreceptors in a
novel transgenic mouse (P2X7null/rd1 mouse).”
Dr Fletcher and Dr Una
Greferath, who was also supported last year, spoke at the
Annual General Meetings of RA (NSW) and RA (Victoria) at the
end of the year. They have kindly written a report of their
work for RODS readers and for the RP organizations
Retina Australia also
allocated grants to:
The Eye Genetics Research Group at The Children’s Hospital
at Westmead and the University of Sydney.
Investigators: Associate Professor Robyn Jamieson; Dr John
Centre for Eye Research Australia
(Affiliated with the University of Melbourne and the
Royal Victorian Eye and Ear Hospital).
Professor Robyn Guymer; Dr Lyndell Lim.
The University of Western
Professors David M Hunt and Shaun P Collin.
RECENT DEVELOPMENTS IN RETINAL
Professor Erica Fletcher, Dr Ursula Greferath, University of
There have been considerable
advances in our knowledge of the pathogenesis of inherited
retinal degenerations over the last five years that have
lead to the development of some very promising treatments.
Below, we have summarized some of our own findings examining
new animal models of inherited retinal degeneration, ways to
slow photoreceptor death and also novel ways of replacing
1) New animal models:
Most research into the mechanisms of photoreceptor death
have utilized animal models that carry mutations in rod
associated proteins (e.g., rhodopsin). Whilst this work has
been very important, it has little relevance to some of the
rarer forms of retinal degeneration such as Leber Congenital
Amaurosis. Recently, we have identified a novel mouse that
replicates many of the features of one form of Leber
Congenital Amaurosis. This mouse called the Histidine
decarboxylase null mouse develops severe changes in the
outer retina because the support cells of the retina lack
proteins that maintain the correct position of the rods and
cones. These mice will be used by us now to study some of
the rarer forms of retinal degeneration.
Slowing photoreceptor death:
much of our work over the last few years has been directed
at examining whether dying rods release a toxic factor that
affects neighbouring photoreceptors. Our work has shown that
the energy molecule, ATP is released in large amounts from
dying rods and accelerates the death of neighbouring cells.
We have tested two drugs known to block the action of ATP,
and shown them to slow photoreceptor death in a mouse model
of retinal degeneration. In addition, we have found that the
rate of photoreceptor death is slowed in transgenic mice
that lack the expression of the receptor to ATP. Agents that
block the action of ATP are under development by large
pharmaceutical companies because of their potential role in
controlling some forms of pain. We hope our work expands the
possible uses of these compounds into the ophthalmic area.
3) Novel ways of
replacing lost photoreceptors:
The two most exciting
developments to restore vision in those who have few
photoreceptors remaining are the development of electronic
implants, and the use of gene therapy to target visual
pigments to the remaining neurons of the inner retina. There
are currently two large groups in Australia developing
electronic implants to restore vision. One group is
designing retinal implants: a wide-field device that sits
underneath the retina, and another high visual acuity device
that is designed to target the output neurons of the retina.
It is hoped that trials for the wide view device in patients
will begin in the next year. The high visual acuity device
is currently undergoing preclinical testing. A second group,
based at Monash University is designing an implant to be
inserted into the visual area of the brain. This device is
intended to restore vision in those who have no remaining
ganglion cells or an intact optic nerve. Currently this
device is undergoing extensive preclinical development.
Gene therapy has been used to
target visual pigment to inner retinal neurons. The inner
retina of those with inherited retinal degeneration is
usually intact. By using gene therapy, inner retinal neurons
can become light sensitive, performing the duties of
photoreceptors. These studies are very exciting because the
technology can be used in most patients with inherited
retinal degeneration irrespective of the specific genetic
cause of the disease.
In summary, over the last few
years our knowledge of inherited retinal degeneration has
increased dramatically, to the point where treatments are
now being tested in patients, with exciting results.
Ex vivo Gene Therapy and Vision
Department of Ophthalmology & Visual Science,
University of British Columbia, Eye Care Centre, 2550 Willow
Street, Vancouver, BC, Canada.V5Z3N9.
Gregory-Evans K, Bashar AE, Tan M.
Ex vivo gene therapy, a technique where
genetic manipulation of cells is undertaken remotely and
more safely since it is outside the body, is an emerging
therapeutic strategy particularly well suited to targeting a
specific organ rather than for treating a whole organism.
The eye and visual pathways therefore make an attractive
target for this approach. With blindness still so prevalent
worldwide, new approaches to treatment would also be widely
applicable and a significant advance in improving quality of
life. Despite being a relatively new approach, ex vivo gene
therapy has already achieved significant advances in the
treatment of blindness in pre-clinical trials. In
particular, advances are being achieved in corneal disease,
glaucoma, retinal degeneration, stroke and multiple
sclerosis through genetic re-programming of cells to replace
degenerate cells and through more refined neuroprotection,
modulation of inflammation and replacement of deficient
protein. In this review we discuss the latest developments
in exvivo gene therapy relevant to the visual pathways and
highlight the challenges that need to be overcome for
progress into clinical trials.