[il-talk] RP Research from National Institutes of Health

Thu Jul 2 19:15:46 UTC 2015

I just came across this article and thought some people on this list might
be interested. Apparently NIH is looking for participants in a clinical
trial for a new RP treatment.

Debbie S.

For Immediate Release: Thursday, July 2, 2015

In blinding eye disease, trash-collecting cells go awry, accelerate damage

NIH research points to microglia as potential therapeutic target in
retinitis pigmentosa

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Spider-like cells inside the brain, spinal cord and eye hunt for invaders,
capturing and then devouring them. These cells, called microglia, often play
a beneficial role by helping to clear trash and protect the central nervous
system against infection. But a new study by researchers at the National Eye
Institute (NEI) shows that they also accelerate damage wrought by blinding
eye disorders, such as retinitis pigmentosa. NEI is part of the National
Institutes of Health.

"These findings are important because they suggest that microglia may
provide a target for entirely new therapeutic strategies aimed at halting
blinding eye diseases of the retina," said NEI Director, Paul A. Sieving,
M.D. "New targets create untapped opportunities for preventing
disease-related damage to the eye, and preserving vision for as long as
possible." The findings were published in the journal EMBO Molecular
Medicine.

Retinitis pigmentosa, an inherited disorder that affects roughly 1 in 4,000
people, damages the retina, the light-sensitive tissue at the back of the
eye. Research has shown links between retinitis pigmentosa and several
mutations in genes for photoreceptors, the cells in the retina that convert
light into electrical signals that are sent to the brain via the optic
nerve. In the early stages of the disease, rod photoreceptors, which enable
us to see in low light, are lost, causing night blindness.  As the disease
progresses, cone photoreceptors, which are needed for sharp vision and
seeing colors, can also die off, eventually leading to complete blindness.

Lead investigator, Wai T. Wong M.D., Ph.D., chief of the Unit on Neuron-Glia
Interactions in Retinal Disease at NEI, and his team studied mice with a
mutation in a gene that can also cause retinitis pigmentosa in people. The
researchers observed in these mice that very early in the disease process,
the microglia infiltrate a layer of the retina near the photoreceptors,
called the outer nuclear layer, where they don't usually venture.  The
microglia then create a cup-like structure over a single photoreceptor,
surrounding it to ingest it in a process called phagocytosis. Wong and his
team caught this dynamic process on video. The whole feast, including
digestion, takes about an hour. 

Phagocytosis is a normal process in healthy tissues and is a key way of
clearing away dead cells and cellular debris. However, in retinitis
pigmentosa the researchers found that the microglia target damaged but
living photoreceptors, in addition to dead ones. To confirm that microglia
contribute to the degeneration process, the researchers genetically
eliminated the microglia, which slowed the rate of rod photoreceptor death
and the loss of visual function in the mice. Inhibiting phagocytosis with a
compound had a similar effect. The microglia seem to ignore cone
photoreceptors, which fits with the known early course of retinitis
pigmentosa. 

A microglial cell (green) extends spider-like arms to capture and consume
rod photoreceptor cells (blue). Credit: Dr. Wai Wong, NEI.

"These findings suggest that therapeutic strategies that inhibit microglial
activation may help decelerate the rate of rod photoreceptor degeneration
and preserve vision," Wong said.

What triggers microglia to go on this destructive feeding frenzy? Wong and
colleagues found evidence that photoreceptors carrying mutations undergo
physiological stress.  The stress then triggers them to secrete chemicals
dubbed "find me" signals, which is like ringing a dinner bell that attracts
microglia into the retinal layer. Once there, the microglia probe the
photoreceptors repeatedly, exposing themselves to "eat me" signals, which
then trigger phagocytosis. In response to all the feasting, the microglia
become activated. That is, they send out their own signals to call other
microglia to the scene and they release substances that promote
inflammation.

Other potential treatments for retinitis pigmentosa, such as gene therapy,
are progressing, but are not without challenges. Gene therapy requires
replacing defective genes with functional genes, yet more than 50 distinct
genes have been linked to the disease in different families, so there's no
one-size-fits-all gene therapy. A therapy targeting microglia might
complement gene therapy because it's an approach that's independent of the
specific genetic cause of retinitis pigmentosa, said Wong. 

A clinical trial (NCT02140164
<https://www.clinicaltrials.gov/ct2/show/NCT02140164?term=NCT02140164&rank=1
> ) is already underway at NEI to see if the anti-inflammatory drug
minocycline can block the activation of microglia and help slow the
progression of retinitis pigmentosa.  The trial is currently recruiting
participants. 

Wong's lab colleagues Lian Zhao, Ph.D., Matthew Zabel, Ph.D., and Xu Wang,
M.D., Ph.D., played key roles in conceiving and conducting this research. To
hear Zabel talk about his work on retinitis pigmentosa, watch this video
from NIH and LabTV <https://youtu.be/ZKylYn7qhyg>
<http://www.nih.gov/exitdisclaimer.html> .

To watch a video of microglia eating rod photoreceptors, go to
http://youtu.be/xXmUGYCi7rE  <http://www.nih.gov/exitdisclaimer.html> . 

This research was supported by the National Eye Institute Intramural
Research Program and grant NS087198 from NIH's National Institute of
Neurological Disorders and Stroke.

NEI leads the federal government's research on the visual system and eye
diseases. NEI supports basic and clinical science programs that result in
the development of sight-saving treatments. For more information, visit
http://www.nei.nih.gov <http://www.nei.nih.gov/> .

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