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Glaucoma therapy targets apoptosis
and trabecular meshwork
By
Laszlo Dosa
WASHINGTON, DC - New vectors may improve prospects for glaucoma
gene therapy aimed at delivering proteins to inhibit programmed
cell death or apoptosis, announced Stuart J. McKinnon MD, PhD at
a Research to Prevent Blindness Foundation seminar.
Dr McKinnon's research focuses on the "suicide" of retinal
ganglion cells believed to be an essential part of the pathogenesis
of glaucoma.
He first attempted to introduce the therapeutic proteins via an
adenovirus vector but found adenovirus has very little impact on
the retina.
Fortunately, a collaborative effort with William Hauswirth PhD,
University of Florida, Gainesville, US, has provided the solution.
"Dr Hauswirth has developed adeno-associated virus (AAV) vectors
and in one of these he incorporated a gene that produces a protein
which prevents apoptosis in these retinal ganglion cells.
An
optic nerve cross-section from a representative hypertensive eye
injected with control vector construct AAV-GFP
(above left) compared to the paired control (above r) shows gliosis
and profound axon loss. The optic nerve from a representative hypertensive
eye injected with AAV-BIRC4 (below left) shows relative protection
of optic nerve axons compared to the AAV-GFP hypertensive eye (above
r) and paired control eye (below r). Scale bar = 0.0 mm.
"The
gene is called the x-linked inhibitor of apoptosis protein or XIAP.
It is also known as BIRC4," Dr McKinnon explained.
The researchers tested the gene and its delivery vehicle on rats
with induced glaucoma. The XIAP gene reached its destination in
the ganglion cells and expressed the desired protein.
After about three months of exposure, the researchers looked at
the number of axons in the optic nerves of each animal and found
that, on average, the genetic treatment protected 50% of optic nerve
axons in the rat glaucoma model.
That may seem like an incomplete rescue, but it is an important
first step, Dr McKinnon told EuroTimes.
"Fortunately, people really don't lose vision as we measure
it until they've lost 30% to 50% of their ganglion cells. So if
we can protect 50%, I believe we can actually maintain visual function,"
he said.
The gene therapy works by inhibiting the activation of proteases,
known as caspases, which kill cells by degrading structural proteins
and DNA.
Interestingly, caspases also play a role in Alzheimer's disease,
which may help explain why the incidence of glaucoma is significantly
higher among Alzheimer patients.
"Dr McKinnon's work is extremely interesting because the gene
he puts into cells is an inhibitor of caspases. It seems to be a
very promising approach to turn off the death programme in ganglion
cells and rescue them," Larry I. Benowitz PhD said.
Terete Borrás PhD uses a different approach to treat glaucoma.
She is looking at the feasibility of gene transfer to modify the
physiology of the trabecular meshwork, which maintains pressure
inside the eye by impeding the continuous flow of aqueous humour.
"We have shown that a single dose of recombinant adenoviral
vectors, delivered by intracameral injection, transfers reporter
genes very efficiently to all cell types of the trabecular meshwork,"
Dr Borrás reported.
She said in living rodents, positive gene transfer lasts for about
three weeks but the expression of the foreign gene can be extended
for a longer period and the transfer itself can be repeated.
In in vitro experiments with human donor eye cultures, Dr Borrás
has found that just one gene will enhance fluid outflow.
The next step will be to extend the length of expression of the
delivered gene up to six months to one year, with the ultimate goal
being to develop a glaucoma therapy.
Currently, compliance among glaucoma patients who must take several
medications each day is poor.
"Our goal is to see if we can reduce the treatment to once
a week," Dr Borrás said.
She added that because glaucoma is a complex disease, multiple genes
are likely to be good candidates for gene therapy.
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