Retinoid therapy may improve vision in people with rare genetic disorder


Date:
November 9, 2021
Source:
University of Maryland School of Medicine
Summary:
Using data generated from patients and mice with genetic mutation
for the disorder Usher syndrome, researchers documented the natural
history of vision impairment in patients and identified the cell
mechanism behind progressive vision loss. Based on these findings,
the team was able to test a retinoid therapy that improved vision
in mice with Usher syndrome.

The researchers said assessing a similar therapy should now be
considered in people with Usher syndrome to see if this therapy
might slow vision loss.



FULL STORY ========================================================================== Using data generated from patients and mice with genetic mutation
for the disorder Usher syndrome, researchers from the University of
Maryland School of Medicine (UMSOM), the National Institutes of Health's National Eye Institute (NEI), and National Institute on Deafness and
Other Communication Disorders (NIDCD), documented the natural history of
vision impairment in patients and identified the cell mechanism behind progressive vision loss.


========================================================================== Based on these findings, published on November 9, 2021, in the journal
eLife, the team was able to test a retinoid therapy that improved vision
in mice with Usher syndrome. The researchers said assessing a similar
therapy should now be considered in people with Usher syndrome to see
if this therapy might slow vision loss.

Usher syndrome type 1F (USH1F) causes deafness, progressive vision loss,
and balance issues. Among Ashkenazi Jews, there is a 2% chance each
person is a carrier of the Usher syndrome type 1F mutation, accounting
for approximately 60% of their Usher syndrome type 1 cases. There are
no approved therapies to prevent vision loss or restore vision in people
with Usher syndrome.

"The drug we used in mice may provide a first step to improve eye health
in people with Usher syndrome type 1F," said Zubair M. Ahmed, PhD,
Professor of Otorhinolaryngology -- Head & Neck Surgery and Ophthalmology
at UMSOM.

"Unfortunately, these drugs will not permanently cure loss of vision,
as the drug does not repair damage or prevent degeneration of the
eyes. However, it should improve the function of the tissue that these
patients still have." First author of the study Saumil Sethna, PhD,
Instructor in Otorhinolaryngology -- Head & Neck Surgery, said, "There
are currently FDA-approved relatives of these retinoid drugs that are
available and have passed clinical trials for safety, along with others
that are in phase II clinical trials to treat other types of vision loss disorders." The team hopes to partner with one of the companies testing
these drugs to launch a clinical trial in patients with Usher syndrome
type 1F to see if it can help by preventing continuing vision loss.



==========================================================================
"The identification of a key mutation in the PCDH15gene nearly two
decades ago was a critical breakthrough, facilitating the diagnosis of
and carrier screening for a certain form of Usher syndrome, now resulting
in the discovery of a potential preventative therapy for vision loss
associated with the syndrome," said Thomas B. Friedman, Ph.D., Chief of
the Laboratory of Molecular Genetics at the NIDCD. "This work exemplifies
the value of basic science research in driving the development of novel diagnostics and therapeutics." Prior to this study, only anecdotal
data had been reported for Usher syndrome type 1F without any detailed
data analysis of the worsening eye abnormalities over time. In the
early 2000s, co-authors on this study, including Dr. Friedman at NIDCD, initiated an Usher syndrome natural history project and enrolled 13 study participants with Usher syndrome 1F to follow the natural progression
of their accompanying blindness over 20 or more years. Dr. Ahmed was
a Postdoctoral Fellow in Dr. Friedman's laboratory at the time. Wadih
Zein, MD, an NEI Ophthalmologist with expertise in inherited retinal degenerations, served as principal investigator on the natural history
study and summarized patient findings collected over the years. Based
on analysis of vision tests, Dr. Zein found that the Usher syndrome type
1F mutation led to 50% of the study participants being legally blind by
age 50.

Separately, Dr. Ahmed created a mouse with an Usher syndrome found in
13 of Dr.

Friedman's patients. This mutation in the gene PCDH15leads to a shortened version of the protein protocadherin-15. However, the mechanism for how
this mutant protocadherin-15 led to blindness was unknown. To unravel
this, Dr.

Friedman's Dr. Zein's, and Dr. Ahmed's teams decided to collaborate and
compare the eye characteristics from humans and mice with this genetic condition that they had independently collected over the years.

Comparing the Usher syndrome mouse model to healthy mice, Dr. Ahmed's
team identified two functions of protocadherin-15. First, Protocadherin-15 helps light-dark cycle proteins move back and forth between the different compartments of the light-detecting photoreceptors in the eye. Second, Protocadherin-15 is also required for recycling molecules essential for functioning eye tissue, known as retinoids. The Usher syndrome type 1F
mutant mice had reduced levels of retinoids in a certain kind of eye cell.

Next, the researchers gave a retinoid drug to the Usher syndrome mice
to see if it improved their vision. Retinoid injections into the Usher
syndrome mice increased the electrical activity in the eyes of both
younger and adult mice, indicating improved vision function.

"Aside from retinoid replacement, we can also think about developing
more permanent therapies to treat or prevent blindness in people with
Usher syndrome type 1F that may correct or replace the other functions
of protocadherin-15, as well," said Dr. Ahmed.

E. Albert Reece, MD, PhD, MBA, Executive Vice President for
Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School
of Medicine said, "People born with deafness, like individuals
with Usher syndrome, rely on their other senses to communicate
with and understand the world. Subsequent vision loss can pose
significant challenges and can be isolating. This work here
builds foundational discoveries that may one day improve the
lives of people with rare genetic disorders such as Usher syndrome." ========================================================================== Story Source: Materials provided by
University_of_Maryland_School_of_Medicine. Original written by Vanessa
McMains. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Saumil Sethna, Wadih M Zein, Sehar Riaz, Arnaud PJ Giese, Julie M
Schultz, Todd Duncan, Robert B Hufnagel, Carmen C Brewer,
Andrew J Griffith, T Michael Redmond, Saima Riazuddin, Thomas
B Friedman, Zubair M Ahmed. Proposed therapy, developed in a
Pcdh15-deficient mouse, for progressive loss of vision in human
Usher syndrome. eLife, 2021; 10 DOI: 10.7554/eLife.67361 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211109120606.htm

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