Drug made from pig intestine helps escape the 'trap' of clot-causing
immune response
The findings may set the stage for defibrotide clinical trials in
potentially several diseases

Date:
December 9, 2021
Source:
Michigan Medicine - University of Michigan
Summary:
Two complementary studies show that defibrotide can successfully
suppress the formation and progression of neutrophil extracellular
traps, or NETs, which are web-like networks of toxic proteins
that play a role in forming blood clots and promoting inflammation
in several disease, including COVID-19. Researchers say findings
may set the stage for defibrotide clinical trials in potentially
several diseases.



FULL STORY ==========================================================================
When the body attempts to fight off an infection, immune cells called neutrophils may shoot out spider web-like networks of toxic proteins
to help contain the invaders. However, when not properly regulated,
these web-like neutrophil extracellular traps, or NETs, play a role in
forming blood clots and promoting inflammation for several diseases,
including COVID-19.


========================================================================== Utilizing the uncommon drug defibrotide, researchers recently found
success at stopping the formation and progression of the noxious
NETs. Defibrotide is a complex mixture of short DNA fragments -- purified
from the cells of pig intestines. It's currently used to treat blockages
in the liver's blood vessels after stem cell transplantation.

NETs are major contributors to blood clotting in patients with an
autoimmune disease known as antiphospholipid syndrome, also commonly
referred to as APS.

Defibrotide was first reported as a possible treatment for a
life-threatening form of APS some 20 years ago, but the mechanism was
unknown.

Inspired by this observation, a team of rheumatologists at Michigan
Medicine recently tested how defibrotide interacted with immune
cells. They found not only that the treatment suppressed neutrophils
from releasing NETs, but it also reduced downstream blood-clotting in
mice with APS, according to results published in Arthritis & Rheumatology.

The treatment was so effective at neutralizing NETs and thrombosis that
it made mice with APS look and behave like completely healthy mice,
said Jason Knight, M.D., Ph.D., senior author of the paper and associate professor of rheumatology at Michigan Medicine.

"This could be significant for the severest forms of APS, the cases that
land people in the hospital where they require emergency treatment,"
Knight said.

"Progress was stalled on proper clinical trials given little understanding
of the mechanisms by which defibrotide helped APS. We hope this work will contribute to changing that." The first and only case of defibrotide and
APS was written 20 years ago by Doruk Erkan, M.D. M.P.H., a co-author
of the paper and rheumatologist at the Hospital for Special Surgery in
New York City.



========================================================================== "This study is historic," Erkan said. "Two decades after the only case
report of defibrotide use in catastrophic APS, now we have scientific
support about how it may interfere with APS-associated thrombosis."
In a separate complementary study, published in JCI Insight, Knight's
team found that beyond NET release, defibrotide also effectively
neutralized NETs once they had already formed. The team found that
the biochemical properties of the defibrotide molecule make it ideally
suited to bind histones, one of the most toxic types of proteins found
in NETs. Histones are known to activate the lining of the blood vessels
and cause blood clots.

"Because the defibrotide molecule has a negative charge, it is really
effective at suppressing the histones, serving as a kind of sponge that
soaks up this toxic part of the NETs and thereby prevents the activation
of blood vessel cells," Knight said. "This property of defibrotide
might have broad use for many diseases where NETs cause inflammation
and clotting." One example presented itself last year when researchers, including Knight's group, found that the most severe COVID-19 patients
had higher levels of NETs.

The web-like traps also play damaging roles in a variety of other diseases ranging from autoimmune conditions to cancer.

"While more research needs to be conducted, the hope is that drugs
like defibrotide can prevent inflammatory types of blood clotting,
sometimes called immunothrombosis, in a way that will not increase the
risk of bleeding," said Knight. "That's really the Holy Grail, and we
hope this gets us one step closer." Disclosure: For both studies, Jazz Pharmaceuticals provided funding for the preclinical experiments but
did not have any input regarding the experimental design or data analysis.

========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Noah
Fromson. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Ramadan A. Ali, Shanea K. Estes, Alex A. Gandhi, Srilakshmi
Yalavarthi,
Claire K. Hoy, Hui Shi, Yu Zuo, Doruk Erkan, Jason
S. Knight. Defibrotide inhibits antiphospholipid
antibody‐mediated NET formation and venous
thrombosis. Arthritis & Rheumatology, 2021; DOI: 10.1002/art.42017
2. Hui Shi, Alex A. Gandhi, Stephanie A. Smith, Qiuyu Wang, Diane
Chiang,
Srilakshmi Yalavarthi, Ramadan A. Ali, Chao Liu, Gautam Sule,
Pei-Suen Tsou, Yu Zuo, Yogendra Kanthi, Evan A. Farkash, Jiandie
D. Lin, James H.

Morrissey, Jason S. Knight. Endothelium-protective,
histone-neutralizing properties of the polyanionic
agent defibrotide. JCI Insight, 2021; 6 (17) DOI:
10.1172/jci.insight.149149 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211209082555.htm

--- up 5 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)