"Reverse-Engineering" of Existing Compound
Yields Potential New Therapy
NEW
YORK, June 8, 2023 /PRNewswire/ -- An
experimental drug already tested as a potential treatment for
cancer, lung, and Alzheimer's disease may slow the progression of
atherosclerosis that leads to heart disease, a new study shows.
Led by researchers at NYU Grossman School of Medicine, the study
explored the mechanisms behind atherosclerosis, in which fatty
deposits build up in blood vessels. As this buildup hardens into
plaques and causes misplaced immune reactions (inflammation), it
can block blood flow to cause heart attack or stroke.
Publishing June 8 in the journal
Nature Cardiovascular Research, the new study showed that
plasma (the liquid part of blood) from patients with
atherosclerotic disease triggers an usually high inflammatory
signal in blood immune cells. Further experiments then showed that
the drug saracatinib reduced this inflammation signaling by more
than 90% in human blood samples and diseased tissue samples.
"Our findings provide new insight into the inflammatory
mechanisms in atherosclerosis and suggest for the first time that
saracatinib may offer an effective therapy in cases where standard
therapy, in the form of statins, fails to help," says study co-lead
author Letizia Amadori, PhD, a
senior research scientist at NYU Langone Health.
Physicians prescribe statins to reduce harmful fats in the
blood, but studies show that even with reduced plaque deposits,
inflammation persists in many patients, who remain at high risk for
heart attack. According to the study authors, the causes of this
chronic immune response in patients are not fully understood, and
anti-inflammatory treatments are sometimes ineffective in patient
studies.
For the study, the team analyzed blood samples from 34 men and
women with the condition specifically termed atherosclerotic
cardiovascular disease (ASCVD), all of whom were on statins, and
compared them with samples from 24 healthy donors.
To home in on saracatinib, the study authors explored 4,823
genes including 277 already known to play a role in inflammation
and produce cytokines and other proteins that promote a chronic
immune response.
According to Amadori, the team reasoned that if a particular
medication could stop all these molecules from being made, then it
could calm the response.
Rather than trying to create a suitable drug from scratch, the
researchers instead turned to a list of pharmaceuticals already
approved or being tested for other uses. Specifically, they
searched a series of datasets from the National Institutes of
Health called the Library of Integrated Network-Based Cellular
Signatures, which contains hundreds of thousands of test results
mapping the effects of various molecules, signaling proteins, and
genetic changes on human cells.
Because saracatinib was shown in this search to reverse the
expression of target genes, the process by which genes are turned
on to make proteins, the authors tested it in human cells, diseased
tissue, and animal models to see if it could actually stop, slow,
or reverse inflammation prompted by ASCVD.
Among the findings, the results revealed that saracatinib blocks
gene activity responsible for producing inflammatory proteins such
as interleukin-1 beta and interluekin-6 that maintain ASCVD's
immune reactivity. Notably, an inhibitor of interleukin-1 beta was
shown to effectively prevent heart attack in an earlier trial. At
the same time, the drug boosted genes known to make proteins that
help clean up plaque deposits by transporting fat away from the
arteries.
Further experiments in rabbits revealed that saracatinib reduced
plaque-based inflammation by about 97% compared with untreated
animals. Meanwhile in mice, the same therapy prompted up to an 80%
reduction in cells linked to inflammation in plaques and shrunk
plaque deposits between 48% and 70%, depending on the dose of the
medication, says Amadori.
"Our reverse-engineering method of finding new uses for old
drugs can in theory be harnessed to uncover therapies for
practically any disease that involves inflammation," said study
senior author Chiara Giannarelli,
MD, PhD. "Since these chemicals have already been tested for
safety, this technique offers a swift and cost-effective approach
to pharmaceutical development."
Giannarelli, an associate professor in the Departments of
Medicine and Pathology at NYU Langone, says the study team next
plans to use their same protocol to explore potential treatments
for other inflammatory conditions linked to ASCVD, such as
rheumatic arthritis or type 2 diabetes.
That said, Giannarelli cautions that while saracatinib appears
promising, it must still be clinically tested to ensure that the
treatment actually works in patients.
Funding for the study was provided by National Institutes of
Health (NIH) grants UH2TR002067 and UH3TR002067. Additional support
was provided by NIH grants R21TR001739, R01HL153712, T32HL007824,
R35HL135799, P01HL131481, R01HL143814, R01HL140072, RC2DK131995,
R01DK131525, OT2OD030160, and U54HL127624.
Giannarelli is an inventor of a patent pending (Tech 160808G
PCT/US2022/017777) for this therapeutic approach to treat ASCVD as
well as for the team's drug development pathway. The terms and
conditions are being managed in accordance with the policies and
practices of the Icahn School of Medicine at Mount Sinai and NYU Langone Health.
In addition to Amadori and Giannarelli, other NYU researchers involved in the study were
Ravneet Kaur, MS; Swathy Sajja, MS; Roza Shamailova, MA;
Yannick Cyr, PhD; Natalia Eberhardt, PhD; and Kathryn Moore, PhD. Other investigators involved
in the study are Dawn Fernandez,
PhD; Simon Koplev, MS; Nicolas
Fernandez, PhD; Pauline Mury,
PhD; Nayaab Kahn, PhD; Minji Jeon,
PhD; Christopher Hill, BA;
Peik Sean Chong, MS; Sonum Naidu,
BSE; Ken Sakurai, PhD; Adam Ghotbi, MD, PhD; Raphael Soler, MD, PhD; Adeeb Rahman, PhD; Peter
Faries, MD; Zahi Fayad, PhD;
and Avi Ma'ayan, PhD; at the Icahn
School of Medicine at Mount Sinai
in New York City. Claudia Calcagno, MD, PhD, also at Mount Sinai, served as study co-lead
author.
Media Inquiries
Shira Polan
212-404-4279
shira.polan@nyulangone.org
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SOURCE NYU Langone Health
