Seeing corneal degeneration in a new light
Seeing what happens over the decades it takes for one eye disease to
develop and cause symptoms

Date:
June 17, 2020
Source:
UT Southwestern Medical Center
Summary:
The molecular changes that lead to Fuchs' endothelial corneal
dystrophy (FECD) occur decades before the disease causes blurry
vision and other noticeable symptoms in patients, new research
shows. This insight into this earliest stage of FECD may eventually
lead to new ways of screening for and treating the common condition,
which affects an estimated 4 percent of U.S. adults over the age
of 40.



FULL STORY ==========================================================================
The molecular changes that lead to Fuchs' endothelial corneal dystrophy
(FECD) occur decades before the disease causes blurry vision and
other noticeable symptoms in patients, new research by UT Southwestern scientists shows. This insight into this earliest stage of FECD may
eventually lead to new ways of screening for and treating the common
condition, which affects an estimated 4 percent of U.S. adults over the
age of 40.


==========================================================================
"We found changes in the pre-symptomatic tissue that would not be
readily apparent to ophthalmologists who are examining patients," says
Vinod Mootha, M.D., a professor of ophthalmology at UTSW and a co-senior
author of the study.

"This molecular cascade of events is initiated decades before we usually
detect disease in the clinic." FECD is an age-related, degenerative
disease of the cornea -- the clear outer layer of the eye. Patients with
FECD, which usually affects both eyes at once, experience swelling of
the cornea, leading to discomfort and blurry vision.

Over the last decade, Mootha has helped uncover the genetic and molecular drivers of FECD. In 2015, his laboratory co-discovered that most cases
of late- onset FECD, appearing in people in their 50s and 60s, are caused
by a repetitive section of DNA that gives rise to toxic accumulations of
repeat RNA in corneal tissue. The TCF4 gene harbors a three-nucleotide
repeat; the number of times this repeat occurs varies among individuals,
and people who have more than 40 of the repeats are at the highest risk
of FECD. The mechanism is similar to that of other diseases known as degenerative trinucleotide repeat diseases, which include Huntington's
and some forms of amyotrophic lateral sclerosis (ALS).

"For most trinucleotide repeat diseases, it's impossible to obtain
affected tissue, and very hard to study the early stages of disease,"
says David Corey, Ph.D., a professor of pharmacology and biochemistry
who holds the Rusty Kelley Professorship in Medical Science at UTSW and
a co-senior author of the study.

"But with the eye, we can actually look at human tissue samples
quite easily." In the paper, published in the journal Nucleic Acids
Research, Corey, an expert in trinucleotide repeat diseases, teamed up
with Mootha to better understand how the repeats in TCF4lead to corneal degeneration. The researchers compared corneal tissue collected during
eye surgery from 10 FECD patients with healthy post-mortem tissue from
nine eye bank donors. In addition, while screening eye bank samples for inclusion in the study, the researchers discovered six people who had
the genetic predisposition for FECD but no outward signs of disease on
their corneas yet.



==========================================================================
When the researchers compared the patterns of gene expression in the three groups of eye tissue, they pinpointed a number of molecular changes in
the corneas of people diagnosed with FECD. Moreover, many of those same
changes were already measurable in the eyes of people with the gene for
FECD, even though they hadn't yet developed symptoms.

On average, the FECD patients in the study were 66.5 years old, and the
pre- symptomatic patients from the eye bank samples were 46.8 years old, suggesting that molecular changes occur decades before full-fledged
disease.

"It was really a surprise that the seeds of eventual dysfunction are
sown in the tissue so long before the symptoms are visible," says Corey.

Many of the molecular changes the team identified in the cornea were
related to fibrosis, the thickening and scarring of tissue. That fits with
what ophthalmologists see when they examine the eyes of people with FECD,
says Mootha, and points toward fibrosis molecules and pathways as possible
ways to target the disease with drugs. If levels of the fibrosis-related molecules are altered in the blood of patients before they develop FECD,
for instance, a screening test could be developed.

"Our ultimate goal is to try to slow down or stop the disease process so
that patients don't need corneal transplants," says Mootha. "Based on the results of this study, we have a much better idea of what's happening
early in the disease process, which lets us better track whether we
can reverse those early changes." Corey's research group has already
developed one therapeutic approach for treating trinucleotide repeat
diseases by blocking the repetitive genetic material. They hope to
eventually test that approach on FECD.

Other UTSW researchers who contributed to this study are Yongjun Chu,
Jiaxin Hu, Hanquan Liang, Mohammed Kanchwala, Chao Xing, Walter Beebe,
Charles B.

Bowman, and Xin Gong.

Mootha holds the Paul T. Stoffel/Centex Professorship in Clinical Care.

This research was supported by funds from the National Institutes of
Health (R01EY022161, P30EY030413, and R35GM11810), Research to Prevent Blindness, Harrington Discovery Institute, Alfred and Kathy Gilman
Special Opportunities in Pharmacology Fund, and Welch Foundation I-1244.


========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. V Vinod Mootha, David R Corey, Xin Gong, C Bradley Bowman,
Walter Beebe,
Chao Xing, Mohammed Kanchwala, Hanquan Liang, Jiaxin Hu, Yongjun
Chu.

Analyzing pre-symptomatic tissue to gain insights into the
molecular and mechanistic origins of late-onset degenerative
trinucleotide repeat disease. Nucleic Acids Research, 2020; DOI:
10.1093/nar/gkaa422 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200617174809.htm

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