Molecular link traced from gene to late-onset retinal degeneration
Clinical trial planning underway to test the widely used diabetes drug metformin as a preventive treatment for the blinding eye disease
Date:
December 9, 2021
Source:
NIH/National Eye Institute
Summary:
Scientists have discovered that gene therapy and the diabetes
drug metformin may be potential treatments for late-onset retinal
degeneration (L-ORD), a rare, blinding eye disease. Researchers
generated a 'disease- in-a-dish' model to study the disease.
FULL STORY ========================================================================== Scientists have discovered that gene therapy and the diabetes drug
metformin may be potential treatments for late-onset retinal degeneration (L-ORD), a rare, blinding eye disease. Researchers from the National Eye Institute (NEI), part of the National Institutes of Health generated a "disease-in-a-dish" model to study the disease. The findings are published
in Communications Biology.
========================================================================== "This new model of a rare eye disease is a terrific example
of translational research, where collaboration among clinical and
laboratory researchers advances knowledge not by small steps, but by
leaps and bounds," said Michael F. Chiang, M.D., director of the NEI,
part of the National Institutes of Health.
L-ORD is a rare, dominantly inherited disorder, meaning that it can
occur when there is an abnormal gene from one parent. L-ORD is caused
by a mutation in the gene that encodes the protein CTRP5. People
with the disorder develop abnormal blood vessel growth and deposits
of apolipoprotein E, which is involved in fat metabolism within the
retina. Symptoms, including difficulty seeing in the dark and loss of
central vision, usually appear around age 50 to 60. As L-ORD progresses,
cells in the retinal pigment epithelium (RPE), a layer of tissue that
nourishes the retina's light-sensing photoreceptors, shrink and die. Loss
of RPE leads to the loss of photoreceptors and in turn, to loss of vision.
The investigators were led by Kapil Bharti, Ph.D., who directs the NEI
Ocular and Stem Cell Translational Research Section, and Kiyoharu (Josh) Miyagishima, Ph.D. and Ruchi Sharma, Ph.D., staff scientists in the
section and leading authors of the study. They developed a laboratory
model that uses induced pluripotent stem cells developed from skin (fibroblasts) to make RPE. They generated RPE from two siblings with
L-ORD and, for comparison, RPE from two of the patients' unaffected
siblings who lacked the disease-causing mutation.
The patient-derived RPE shared key characteristics of the disorder in
humans, including deposits of apolipoprotein E near the tissue, and
abnormal secretions of vascular endothelial growth factor, a protein
that stimulates blood vessel growth. The RPE cells also were dysmorphic,
or deformed. By contrast, RPE from the unaffected siblings appeared
normal. The researchers also found that the patient-derived RPE secreted
far less of the mutant and the non-mutant CTRP5 protein compared with
the models made from the unaffected siblings.
Using a computer modeling technique, they showed that mutant CTRP5
was less likely to bind with cell receptors that help fine-tune fat
metabolic regulation. Less receptor binding in turn leads to chronic
activation of AMP- activated protein kinase (AMPK), a key regulator of
energy homeostasis and fat metabolism.
They theorized that when AMPK is chronically activated, it becomes
less sensitive to imbalances in energy demand and nutrient supply. When metabolic imbalances run unchecked, they alter lipid metabolism, which
explains how apolipoprotein E accumulates as deposits near the RPE layer.
Testing that theory, the researchers chemically inhibited the chronically activated AMPK in the patient-derived RPE model and found fewer deposits
of apolipoprotein E, and less abnormal secretion of vascular endothelial
growth factor.
Next, using the patient-derived RPE model, they tested two potential
treatment strategies: A gene therapy approach to encourage expression of
normal CTRP5 in the RPE model, and the use of the diabetes drug metformin, which appears to modulate AMPK activity, re-sensitizing it to changes
in cellular energy status.
Both strategies prevented signs of L-ORD in RPE models.
"Importantly, we now have two potential strategies to disrupt the L-ORD
disease process. While gene therapy may be years away, metformin is a
drug that's long been used to treat diabetes," said Bharti, who with NEI collaborators is planning a clinical trial to test the drug in people
with L-ORD.
Although L-ORD disease is rare, it shares similarities with other retinal degenerations like age-related macular degeneration, a leading cause
of vision loss. The model developed for this study may prove helpful in understanding such age-related disease changes in the RPE.
The study was funded by the NEI Intramural Research Program grants
EY005121 and EY026525.
========================================================================== Story Source: Materials provided by NIH/National_Eye_Institute. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Kiyoharu J. Miyagishima, Ruchi Sharma, Malika Nimmagadda, Katharina
Clore-Gronenborn, Zoya Qureshy, Davide Ortolan, Devika Bose,
Mitra Farnoodian, Congxiao Zhang, Andrew Fausey, Yuri V. Sergeev,
Mones Abu- Asab, Bokkyoo Jun, Khanh V. Do, Marie-Audrey Kautzman
Guerin, Jorgelina Calandria, Aman George, Bin Guan, Qin Wan, Rachel
C. Sharp, Catherine Cukras, Paul A. Sieving, Robert B. Hufnagel,
Nicolas G. Bazan, Kathleen Boesze-Battaglia, Sheldon Miller, Kapil
Bharti. AMPK modulation ameliorates dominant disease phenotypes
of CTRP5 variant in retinal degeneration. Communications Biology,
2021; 4 (1) DOI: 10.1038/s42003- 021-02872-x ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2021/12/211209082603.htm
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