COVID-19 therapy: Better in combination than alone
How a well-known drug can become a game changer
Date:
April 13, 2022
Source:
Charite' - Universita"tsmedizin Berlin
Summary:
There is a steadily growing arsenal of drugs for
COVID-19. Researchers have studied the mechanisms of action of
antiviral and anti-inflammatory drugs. Their findings show that
treatment effects were best with combination therapy involving both
types of drugs. This treatment regimen also had the additional
benefit of increasing the time window available for antibody
therapy.
FULL STORY ========================================================================== There is a steadily growing arsenal of drugs for COVID-19. Researchers
from Charite' -- Universita"tsmedizin Berlin, the Max Delbru"ck Center
for Molecular Medicine (MDC) and Freie Universita"t (FU) Berlin have
studied the mechanisms of action of antiviral and anti-inflammatory
drugs. Their findings, which have been published in Molecular Therapy,show
that treatment effects were best with combination therapy involving both
types of drugs. This treatment regimen also had the additional benefit
of increasing the time window available for antibody therapy.
========================================================================== SARS-CoV-2 infections continue to result in hospitalizations. According
to estimates by the Robert Koch Institute, the current COVID-19
hospitalization rate is approximately six to seven per 100,000 of the
resident population.
Hospitalized COVID-19 patients now have access to a range of drugs which
can reduce the severity of the disease or, in the most severe cases,
reduce the risk of death. Some of these drugs target the virus itself;
others fight the inflammation associated with infection.
First-line treatments include monoclonal antibodies and dexamethasone,
a drug with strong anti-inflammatory properties. Antibody treatments
neutralize the virus by sticking to the surface of its spike protein, preventing it from entering human cells. This type of treatment is used
within seven days after symptom onset. Hospitalized COVID-19 patients who require oxygen therapy usually receive dexamethasone, a glucocorticoid
which, for approximately 60 years, has been used to treat inflammatory conditions caused by an overactive immune response. In COVID-19, too,
the drug has been shown to reliably dampen the body's inflammatory
response. However, as the drug is associated with various side effects, including an increased risk of fungal infections, it should only be used
in a specific and targeted manner.
Researchers from Charite', the MDC's Berlin Institute of Medical Systems Biology (BIMSB) and FU Berlin have now studied the mechanisms of action
of both types of treatment. "We uncovered evidence to suggest that
combination therapy of antibodies and dexamethasone is more effective than either of these treatments alone," says first author Dr. Emanuel Wyler, a researcher at the BIMSB's 'RNA Biology and Posttranscriptional Regulation' research group, which is led Prof. Dr. Markus Landthaler. As not all
lung compartments can be studied using lung tissue samples obtained from patients, the research group's first step last year was to search for
a suitable model. That task fell to co-last author Dr. Jakob Trimpert,
a veterinarian and research group leader at the FU Berlin's Institute
of Virology, who subsequently developed COVID-19 hamster models. As
animals which both contract the same virus variants as humans and develop similar disease symptoms, hamsters have proven the most important non- transgenic model for the study of COVID-19. Symptoms and progression,
however, vary between different species of hamster. While symptoms
usually remain moderate in Syrian hamsters, for example, Roborovski
hamsters will develop severe disease reminiscent of that seen in COVID-19 patients requiring intensive care.
"In the current study, we tested the effects of single and combined
antiviral and anti-inflammatory therapies for COVID-19, meaning we
used the existing models with monoclonal antibodies, dexamethasone,
or a combination of the two," explains Dr. Trimpert. The FU Berlin's
veterinary pathologists then examined infected lung tissue under a
microscope to establish the extent of lung tissue damage. Dr. Trimpert
and his team also determined the quantities of infectious virus and
viral RNA present in the tissues at various time points. This enabled
the researchers to check whether and how viral activity might change
over the course of treatment. "Thanks to a detailed analysis of various COVID-19 parameters, which is only possible in an animal model, we were
able to improve our understanding of the basic mechanisms of action of
two important COVID-19 drugs. Moreover, we found clear evidence of the potential benefits associated with a combination therapy of monoclonal antibodies and dexamethasone," says Dr. Trimpert.
Using single-cell analyses, the researchers demonstrated the drugs'
effects on the complex interplay of various cellular signaling pathways
and the number of immune cells present. Individual cells obtained
from a particular sample were loaded onto a chip, where they were first barcoded and then encapsulated into minute droplets of aqueous fluid. Once prepared, the single cells underwent RNA sequencing, a process used to establish the sequence of genetic building blocks which a cell has just
read. Thanks to barcoding, this RNA is later identifiable as originating
from a particular cell, enabling the researchers to determine cellular
function at the single-cell level with a high degree of accuracy. "We were
able to observe that the antibodies are effective at reducing the amount
of virus present," explains Dr. Wyler. He adds: "This was not much use
in our model, though." This is because it is not the virus that damages
the lung tissue, but the strong inflammatory response triggered by the
virus. The immune cells fighting the invading pathogens release messenger substances to call in reinforcements. When these defensive forces arrive
in large numbers, the lungs can become clogged. "Obstructed blood vessels
and unstable vessel walls can subsequently result in acute lung failure," explains Dr. Wyler.
A surprise came in the shape of the well-known drug dexamethasone. "This
anti- inflammatory exerts a particularly strong effect on a specific kind
of immune cell known as neutrophils," says the study's co-last author
Dr. Geraldine Nouailles, Research Group Leader at Charite''s Department
of Infectious Diseases and Respiratory Medicine. Neutrophils are a type
of white blood cell responsible for mounting a prompt response to viral
and bacterial infections.
"The corticosteroid preparation suppresses the immune system and
prevents the neutrophils from producing messenger substances which would attract other immune cells," explains Dr. Nouailles. She continues:
"This makes the drug extremely effective at preventing an escalation of
the immune response." The best treatment outcomes were achieved when the researchers administered a combination of antiviral and anti-inflammatory treatments. "This type of combination therapy is not included in existing clinical guidelines," emphasizes Dr. Nouailles. "What is more, current
guidance stipulates that, in high-risk patients, antibody therapy can only
be given in the first seven days following symptom onset. In clinical
practice, dexamethasone is only used once a patient requires oxygen
therapy, i.e., at an extremely advanced stage of the disease. Its use in combination, however, opens entirely new treatment time windows." This
new approach must now be evaluated in clinical trials before it can be
adopted in clinical practice.
========================================================================== Story Source: Materials provided by
Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
style and length.
========================================================================== Journal Reference:
1. Emanuel Wyler, Julia M. Adler, Kathrin Eschke, G. Teixeira Alves,
Stefan
Peidli, Fabian Pott, Julia Kazmierski, Laura Michalick, Olivia
Kershaw, Judith Bushe, Sandro Andreotti, Peter Pennitz, Azza
Abdelgawad, Dylan Postmus, Christine Goffinet, Jakob Kreye, S
Momsen Reincke, Harald Pru"ss, Nils Blu"thgen, Achim D. Gruber,
Wolfgang M. Kuebler, Martin Witzenrath, Markus Landthaler,
Geraldine Nouailles, Jakob Trimpert. Key benefits of dexamethasone
and antibody treatment in COVID-19 hamster models revealed
by single-cell transcriptomics. Molecular Therapy, 2022; DOI:
10.1016/j.ymthe.2022.03.014 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220413161825.htm
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