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Putting the squeeze on glaucoma

This story was originally published by Knowable Magazine.

When Sylvia Groth steps through the doors of the Vanderbilt
Eye Institute in Nashville, Tennessee, she knows she has a tough
day ahead. Before she goes home, she’ll very likely have at least
one hard talk with a person whose sight has been ravaged by
glaucoma. “When I make a diagnosis of advanced glaucoma, I do it
with a heavy heart,” she says. “It’s such an empty feeling to not
be able to do anything.”

An incurable eye disease that kills vital nerve cells at the
back of the retina, glaucoma is a leading cause of irreversible blindness in the
world
. More than 70 million people have it, and 3 million of
them already are blind. Nothing can be done to restore vision once
it’s lost, and even the best treatments can’t always slow disease
progression. But researchers foresee a time when they can offer
therapies to protect nerve cells in the eye and perhaps even
restore lost sight.

“We’re making advances with every different type of treatment,”
says ophthalmologist Leonard Levin of McGill University in
Montreal.

Researchers have long understood the basics of the most common
form of glaucoma, called open-angle glaucoma. The eye is nourished
by a clear fluid called the aqueous humor that keeps the eyeball
inflated, plump and healthy. But just like a tire, the eye can
become overinflated. If the aqueous humor can’t drain properly,
pressure inside the eye grows too high and can crush cells within
the optic nerve — the sensory cable that carries images from the
retina to the optical centers of the brain.

Close-up front view photograph of an eye of someone with glaucoma, the lens appears cloudy.

Many people with glaucoma develop high pressure when fluid
builds in the eye. This fluid can push the eye’s lens forward and
may make the cornea waterlogged and cloudy.

CREDIT: CHRIS BARRY / VISUALS UNLIMITED, INC.

Pressure probably hurts nerve cells in other ways too, says
ophthalmologist Harry Quigley of Johns Hopkins University.
While glaucoma causes tell-tale damage to the optic nerve —
including an indentation or “cupping” in the main optic nerve —
other, less obvious types of damage likely vary from one patient to
another.

People with open-angle glaucoma may have no symptoms early on,
even as nerve cells die. Yet as it progresses, glaucoma slowly
erodes peripheral vision, blurring the edges of any scene. Over
time, people may develop “tunnel vision” as if they were looking
through a thin tube or straw. If enough optic nerve cells die,
sight is lost completely. (A less common form of glaucoma can have
immediate, dramatic symptoms, including eye pain, blurriness,
headaches and vomiting).

The oft-seen relationship between glaucoma and eye pressure has
long set the basic approach to therapy. Eye drops and
surgeries that lower pressure can slow or prevent damage. A handful
of new drops have recently been approved by the US Food and Drug
Administration, giving patients and clinicians their first
new options for medication in 20 years. One of
them, Rhopressa, improves outflow of aqueous humor from drainage
tissue at the base of the cornea and is an especially important
advance, Quigley says, because it needs to be used only once a day.
“This is something that patients of mine are trying,” he says.
“It’s for people who are losing their vision but don’t want to try
surgery.”

But the drug also carries potentially strong side effects,
including bloody eyes and blurred vision, making it a poor
choice as a first treatment, adds Quigley, who reviewed the
glaucoma treatment landscape in the 2016 Annual Review of Vision Science.

Diagram shows four stages of glaucoma’s progression, depicted as dark pixels in a gray scale visual field and as blurred dark spots in a simulation of what the patient sees.

As glaucoma progresses, the edges of the visual field blur.
Visual defects, represented as dark pixels (left) and in
simulations of what a person sees (right), increase as the disease
advances.

CREDIT: E. RULLI ET AL / SCIENTIFIC
REPORTS
2018

And reducing pressure isn’t a cure-all. For reasons that aren’t
completely clear, damage to the optic nerve can develop in people
with normal or even low eye pressure. Studies have found that
nearly 30 percent of patients who receive
pressure-relieving treatment for glaucoma go blind in one eye and
nearly 10 percent become legally blind.

“High pressure is the only modifiable risk factor for glaucoma
that we’ve been able to identify,” Groth says. Pressure is “a good
answer and it fits certain patients. But it is not really the whole
answer.”

This growing recognition of glaucoma’s complexities has inspired
researchers to rethink their approach. Instead of merely lowering
pressure inside the eye, they’re looking to bolster and shield the
nerve cells themselves — a tactic called neuroprotection. This
could potentially prevent glaucoma and preserve sight no matter how
much pressure builds in an eye.

“There has been a resurgence of interest in neuroprotection,”
says Levin, coauthor of an overview of the state of research on this
approach
in the 2017 Annual Review of Vision
Science
.

To succeed, scientists will have to shift focus to the nerve
cells involved with vision, he says. “In the old days, the goal was
just to keep the cells alive.” Now, researchers recognize that
cells must not only survive but function as well.

Among a number of candidate treatments are neurotrophic factors,
small molecules the body uses to nurture growing nerve cells. Eye
drops containing recombinant human nerve growth factor (or rhNGF) —
a genetically altered version of a naturally occurring growth
factor — already have been approved by the FDA for treatment of neurotrophic keratitis, a
disease that affects the cornea of the eye. A small, ongoing, 60-patient randomized trial is now testing
rhNGF
in glaucoma patients. The results aren’t yet in, but in
theory, rhNGF could help block a signal that tells an optic nerve
cell it’s time to die, saving the cell and keeping it
functioning.

While much work must be done before these molecules reach
patients, Groth, who was involved in the trial, is excited by the
approach. “We know that they have activating roles on certain
cells,” she says.

Schematic diagram shows what goes wrong in glaucoma. A normal eye is contrasted with an eye with glaucoma in which fluid doesn’t drain properly because of a blockage in the trabecular meshwork.

The most common form of glaucoma, called open-angle glaucoma,
can result when pressure inside the eye builds because of too much
aqueous humor, a fluid that nourishes the eye. The eye may make too
much aqueous humor or it may not drain properly via tissue called
the trabecular meshwork.

CREDIT: IMAGE COURTESY OF MAYO CLINIC

Animal studies of other protective molecules have also shown
promise. Quigley and colleagues found that injections of tozasertib
— a compound that inhibits an enzyme involved in cell death — could
protect the optic nerves of rats with glaucoma,
research he reported in 2013 in the Proceedings of the National
Academy of Sciences
. Quigley’s trying to get pharmaceutical
companies to start clinical trials of the drug but says the process
so far has been slow and frustrating.

At this time, Levin says, there are no large-scale advanced
clinical trials of any potential neuroprotective drugs for
glaucoma, which means that therapies will be several years off.
Still, with so many candidate compounds and so much at stake, he
predicts that major clinical trials could begin within the next one
to three years.

New vision

Protecting the optic nerve against damage would be a huge
accomplishment. But finding a way to restore sight that has been
lost would really change the game. Humans and most other animals
don’t regrow optic nerve cells once they’re damaged, but the genes
involved in building those cells remain. If those genes could
somehow be switched back on — perhaps with a nudge from injected
stem cells, one idea goes — new functioning cells might grow and
sight could return.

So far, researchers have taken only the first steps toward that
dream. It’s possible to grow human optic nerve cells in the lab using
genetically engineered stem cells, a team at Johns Hopkins recently
reported in the journal Stem Cells Translational Medicine.
But, Quigley says, that’s a long way from actually getting those
cells to transfer visual signals to a human brain.

For the foreseeable future, that means surgeries and eye drops
will likely remain the standards for treatment. Those drops can
make a huge difference for people with early-stage glaucoma, but
they need to use them properly and many don’t. In fact, patient
non-compliance is thought to be the main reason eye-drop treatments fail to
slow glaucoma, a team reported in Pharmaceutical Research
in 2019. A separate study involving nearly 14,000 patients
prescribed eye drops for glaucoma found that over the course of a
year, only about 10 percent used the drops without
significant lapses.

Close-up side-by-side photographs a normal optic disc and an enlarged, cupped optic disc in an eye with glaucoma.

The optic nerve carries information from the eye’s retina to the
brain via nerve fibers that exit the back of the eye through the
optic disc. Normally, the center of this optic disc is relatively
small (left), but in an eye with glaucoma, damage to the optic
nerve head manifests as tell-tale “cupping” of the disc
(right).

Because early-stage glaucoma often doesn’t cause symptoms that
interfere with day-to-day life, Quigley says he has a hard time
persuading patients that they should put up with the redness,
irritation and cost that can come with eye drops. “If you give them
a treatment that has any side effects at all, they aren’t going to
abide by that,” he says.

Driving home the importance of early detection and treatment is
a big part of Groth’s job. “There has to be a lot of education to
let patients know what the stakes are,” she says. “I tell my
patients that drops are incredibly important.”

And yet all too often, that goal isn’t met, and some patients
lose sight that might have been saved. Despite these
disappointments, Groth looks to a future that is clearer and
brighter for everyone. “The adage has been that glaucoma is an
irreversible, blinding condition,” she says. “I’d like to hope
that, within my career, I might be privileged to give a different
story to my patients.”

This story was originally published by Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.

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