Toxic DNA buildup in eyes may drive blinding macular degeneration
Common HIV drugs could stop vision loss, research suggests

Date:
September 30, 2021
Source:
University of Virginia Health System
Summary:
Damaging DNA builds up in the eyes of patients with geographic
atrophy, an untreatable, poorly understood form of age-related
macular degeneration that causes blindness, new research
reveals. Based on the discovery, the researchers think it may be
possible to treat the disease with common HIV drugs or an even
safer alternative.



FULL STORY ========================================================================== Damaging DNA builds up in the eyes of patients with geographic atrophy, an untreatable, poorly understood form of age-related macular degeneration
that causes blindness, new research from the University of Virginia
School of Medicine reveals. Based on the discovery, the researchers
think it may be possible to treat the disease with common HIV drugs or
an even safer alternative.


==========================================================================
The harmful DNA, known as Alu cDNA, was previously discovered to be manufactured in the cytoplasm by UVA's Jayakrishna Ambati, MD, and his collaborators. The new findings are believed to be the first time toxic
Alu cDNA accumulation has been confirmed in patients in any disease.

The new findings offer insights into how geographic atrophy progresses
over time. "Although we've known that geographic atrophy expands over
time, we didn't know how or why," said Ambati, of UVA's Department of Ophthalmology and Center for Advanced Vision Science. "Our finding in
human eyes that the levels of toxic Alu cDNA are highest at the leading
edge of the geographic atrophy lesion provides strong evidence that it
is responsible for this expansion over time that leads to vision loss."
About Age-Related Macular Degeneration Geographic atrophy is an advanced
form of age-related macular degeneration, a potentially blinding disease estimated to affect 200 million people around the world. The disease
ultimately destroys vital cells in the retina, the light- sensing portion
of the eye.

Ambati, a top expert in macular degeneration, and his colleagues found
that this destruction is caused by the buildup of Alu DNA, which the researchers discovered floating in the cytoplasm of cells. That Alu
DNA was being manufactured in cytoplasm came as a surprise, as DNA is
typically thought to be contained within the cell nucleus.

As Alu DNA accumulates in the eye, it triggers harmful inflammation via
a part of the immune system called the inflammasome. The researchers
identified how this happens, discovering a previously unknown structural
facet of Alu that triggers the immune mechanism that leads to the death
of the vital retinal cells.

That's where HIV drugs called nucleoside reverse transcriptase inhibitors,
or NRTIs, could come in. The researchers' new work in lab mice suggests
these drugs, or safer derivatives known as Kamuvudines, could block the
harmful inflammation and protect against retinal cell death.

"Over the last two decades, dozens of clinical trials for geographic
atrophy that have targeted other pathways have failed," Ambati
said. "These findings from patient eyes provide a strong impetus for a
new direction." Ambati says his latest findings offer further support
for conducting clinical trials testing the drugs in patients with macular degeneration. A prior study of four different health insurance databases
-- encompassing more than 100 million patients over two decades --
found that people taking NRTIs were almost 40% less likely to develop
dry macular degeneration.

"Our findings from human eyes show that these toxic molecules,
which activate the inflammasome, are most abundant precisely
in the area of greatest disease activity," Ambati said. "We
are very hopeful that a clinical trial of Kamuvudines
will be launched soon in geographic atrophy so that we can
potentially offer a treatment for this devastating condition." ========================================================================== Story Source: Materials provided by
University_of_Virginia_Health_System. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Shinichi Fukuda, Siddharth Narendran, Akhil Varshney, Yosuke
Nagasaka,
Shao-bin Wang, Kameshwari Ambati, Ivana Apicella, Felipe Pereira,
Benjamin J. Fowler, Tetsuhiro Yasuma, Shuichiro Hirahara, Reo
Yasuma, Peirong Huang, Praveen Yerramothu, Ryan D. Makin, Mo Wang,
Kirstie L.

Baker, Kenneth M. Marion, Xiwen Huang, Elmira Baghdasaryan,
Meenakshi Ambati, Vidya L. Ambati, Daipayan Banerjee, Vera
L. Bonilha, Genrich V.

Tolstonog, Ulrike Held, Yuichiro Ogura, Hiroko Terasaki, Tetsuro
Oshika, Deepak Bhattarai, Kyung Bo Kim, Sanford H. Feldman,
J. Ignacio Aguirre, David R. Hinton, Nagaraj Kerur, Srinivas
R. Sadda, Gerald G. Schumann, Bradley D. Gelfand, Jayakrishna
Ambati. Alu complementary DNA is enriched in atrophic macular
degeneration and triggers retinal pigmented epithelium toxicity
via cytosolic innate immunity. Science Advances, 2021; 7 (40)
DOI: 10.1126/sciadv.abj3658 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210930101425.htm

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