Having discovered a genetic trigger for age-related
macular degeneration, the leading cause of
vision loss in people over 50, researchers report that an
experimental state-of-the-art therapy for
treating eye disease could adversely affect the vision of
some patients with the "wrong" genetic
makeup.
In the Aug. 28 online issue of the New England
Journal of Medicine, a multi-institutional team,
including an interdisciplinary contingent from Johns
Hopkins, reports that a mutation in toll-like
receptor 3, or TLR3, a protein known to help cells fight
some types of infection, is associated with
protection from geographic atrophy. Geographic atrophy,
also known as the "dry" form of macular
degeneration, is the progressive shriveling of retinal
cells in the central part of the tissue called the
macula, where cell loss equates to irreversible vision
loss.
The new study implies that there could, in fact, be
adverse consequences in some individuals
who undergo a new treatment using a method called RNA
interference to silence genes in the wet
form of age-related macular degeneration, where growth of
abnormal blood vessels causes vision loss.
RNA interference can be used in some cases to turn off
disease-causing genes. Human trials
using RNAi therapy already are under way for a host of
diseases, including age-related macular
degeneration, or AMD. In theory, turning off a disease gene
is a good idea, but it may not be good for
everyone because everyone differs in their genetic makeup,
cautions Nicholas Katsanis, an associate
professor of
ophthalmology,
molecular biology and genetics and member of the
Institute of Genetic Medicine at the Johns Hopkins
School of Medicine.
"The problem is that if you happen to be an individual
who has the 'wrong' genetic code in TLR3,
you might inadvertently trigger a detrimental effect in
your retina," he said. "You might cure the
individual of one thing and increase their risk in
something else." In this case, he said, it's possible to
cure the wet form of AMD but at the same time increase risk
for the other form.
"This discovery has significant implications for
diagnosing the dry form of [AMD], which is the
most prevalent form, affecting more than 8 million
Americans," said Kang Zhang, a professor of
ophthalmology and human genetics and member of the Shiley
Eye Center at the University of
California, San Diego. "It also allows us to develop new
drugs to treat the dry form of AMD, for which
there currently is no treatment."
In the current report, the team describes experiments
on mouse and human genes showing that
the activity of your TLR3 can determine whether or not
you're afforded a degree of protection from
geographic atrophy. TLR3 is activated in response to viral
infection; it causes infected cells to die.
Based on one's genetic code, some people have more active
TLR3, while others, less active.
"What TLR3 does in the case of infection is sacrifice
an infected cell to protect the
neighborhood," Zhang said.
Biologically well intentioned though the sacrifice may
be, it can lead to blindness.
Based on previous reports hinting to TLR3 involvement
in macular degeneration, Katsanis, Zhang
and colleagues set out to determine whether that link was
real.
By analyzing the DNA of patients in a case-control
study, the researchers not only verified
previously published reports indicating an association
between TLR3 and macular degeneration but also
went on to show a specific association between one "fairly
common" variant of TLR3 and geographic
atrophy. They found that people with specific chemical
difference in the TLR3 protein were less likely
to have geographic atrophy.
To test the assumption that the chemical difference
rendered TLR3 less active, the
researchers next used cells from human eyes containing
either a "normal" or variant version of TLR3.
To activate TLR3, they infected these cells with fake RNA
mimicking genetic material common to
many viruses and measured how many cells died. Fifty
percent fewer cells with the variant version of
TLR3 died compared to cells containing the normal version,
leading the researchers to conclude that
the variant version of TLR3 must be less active and
therefore kills fewer cells.
Finally, to be sure that differences in TLR3 activity
cause similar differences in cell death in
whole eyes (and not just isolated eye cells), they teamed
up with the team of Jayakrishna Ambati, a
professor of physiology, ophthalmology and visual sciences
at the University of Kentucky, and injected
RNA into mice, one set of which was genetically engineered
to have no TLR3. Two weeks later,
researchers examined the mice's eyes and found that those
with TLR3 exhibited 61 percent more
dead eye cells than mice without TLR3, further indicating
that TLR3 activity triggers cells to die, a
process that in turn can lead to geographic atrophy.
"You and me, we have a good 20 [percent] to 30 percent
chance of getting macular
degeneration," Katsanis said. "So when the time comes for
us to start thinking about intervention, we
might want to get genotyped first and then decide what kind
of therapeutic paradigm might be most
appropriate for us."
The researchers say they envision a day when vaccines
might protect us from the viruses that
trigger the pathways that are inappropriately activated or
repressed in models of macular
degeneration. "If we can figure out which viruses might be
acting as triggers, we might be able to find
a way to combat them," Zhang said. "This would be a far
more effective therapy, in my view, than
trying to design a gene therapy approach."
The TLR3 discovery bolsters a growing body of research
that illustrates how genetic
information stratifies individuals for responses to
particular therapies. It is the first involving the
retina.
The research was funded by the National Institutes of
Health, Foundation Fighting Blindness,
Macula Vision Research Foundation, Veterans Affairs Merit
Award, Ruth and Milton Steinbach Fund,
Research to Prevent Blindness, Burroughs Wellcome Fund,
Clinical Scientist Award in Translational
Research and American Health Assistance Foundation.
Other participating researchers are from Johns
Hopkins; UC San Diego; Sichuan Academy of
Medical Sciences and Sichuan Provincial People's Hospital,
Chengdu, China; University of Utah School
of Medicine; Oregon Health & Science University; University
of Kentucky; Greater Baltimore Medical
Center; Keck School of Medicine of the University of
Southern California; and Rockefeller University.