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New study: Montreal researchers identify three drugs that could reduce mortality in severely ill COVID-19 patients – McGill University Health Centre

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Researchers from the RI-MUHC and the McGill Genome Centre examine differences in ICU patients who recovered or died from COVID-19 and identify candidate drugs to treat severe disease.

Montreal, June 1, 2022 – Despite the availability of highly efficacious vaccines, SARS-CoV-2 still causes serious medical complications. The lack of an effective drug treatment for hospitalized patients with severe COVID-19 has contributed to the more than six million deaths worldwide since the beginning of the pandemic, including more than 50,000 deaths in May 2022 alone. To address this therapeutical gap, a team of researchers from the Research Institute of the McGill University Health Centre (RI-MUHC), the Canadian Centre for Computational Genomics (C3G), and the McGill Genome Centre studied host biological responses of patients hospitalized with severe COVID-19, looking for differences between patients who recovered and those who succumbed to the disease. They found that certain cellular pathways were overactivated at the time of intensive care unit (ICU) admission in the deceased patients. The researchers then identified three existing drugs targeting these pathways. Their study, published in Science Advances, provides the required preclinical data to support the testing of these drugs – tacrolimus, zotatifin and nintedanib – in controlled clinical studies.

Vinicius Fava and Mathieu Bourgey, co-first authors of the study

“We identified overactivation of messenger RNA metabolism, RNA splicing and interferon signalling pathways in patients who would not survive,” says Vinicius Fava, PhD, a research associate at the RI-MUHC, co-first author of the study. “The identification by different assays of these differentially activated pathways in the cells of COVID-19 survivors and deceased patients suggests that they are determinants of prognosis and makes them promising targets for pharmacological intervention at the earliest point of hospitalization of critically ill patients.”

Understanding physiology of immune cells in severe COVID-19

The researchers performed a series of cellular and genomic analyses on seven patients hospitalized in the ICU of the McGill University Health Centre, in Montreal, Canada, at the start of the pandemic, between March and April 2020. These patients, of whom three died and four recovered, had the same level of disease severity on the WHO ordinal scale at the time of ICU admission.

The team of researchers characterized the transcriptome (expression of messenger RNA molecule) and the epigenetic landscape (alterations in the DNA structure that affect the ability of cells to regulate gene expression) of the patients’ immune cells at different timepoints: at their admission, at day 5 and at day 15 post admission, to monitor disease evolution. They compared the data between the deceased patients, those who survived and six healthy individuals.

Specifically, the team used single-cell RNA sequencing to understand the cellular composition and the physiological state of Peripheral Blood Mononuclear Cells (PBMCs) following hospitalization. PBMCs are critical components of the immune system that mediate the response to pathogens entering the human body. The analyses focused on three major PBMC cell populations: B cells, myeloid cells and T cells. The team found significant differences in proportions of T cells and myeloid cells between patients who exhibited critical versus moderate symptoms. Critically ill patients at day 5 and day 15 showed a significant reduction of T cells (P = 0.006) and a significant increase of myeloid cells (P = 0.04), suggesting that COVID-19 severity has an impact on PBMC proportions.

David Langlais and Erwin Schurr
David Langlais and Erwin Schurr, co-senior authors of the study

“Our results show a strong correlation of PBMC composition with disease progression. Critically ill patients with poor prognosis showed a significant reduction of T cells and a significant increase of monocytes, consistent with previously reported findings in patients suffering from severe COVID-19,” write the authors of the study.

In contrast, at the time of hospital admission, the researchers detected significant changes in the expression of genes in key molecular pathways that are associated with epigenetic changes in monocytes, a type of white blood cells that transform into macrophages, i.e., cells capable of travelling to an area where an infection is present to kill the pathogen and control proliferation.

“This study confirms the pivotal role of monocytes in COVID-19 severity and disease prognosis, as well as the involvement of interferon pathways in the development of COVID-19,” says David Langlais, PhD, Assistant Professor in McGill’s School of Biomedical Sciences based at the McGill Genome Centre and co-senior author of the study. “It also suggests that variations in transcriptional activity, and the accompanying epigenomics changes, mostly occurred at an early stage of COVID-19 disease, dictating how the disease will evolve in terms of severity and final outcome.”

Repurposing the right drug for the right target

The researchers used various approaches to identify drugs that could suppress the cellular pathways overactivated in monocytes of patients who succumbed to COVID-19.

The initial approach resulted in more than 1500 candidate drugs, which were narrowed down to 53 candidate drugs/compounds previously used to treat cancers and/or inflammatory conditions. Using drug-protein and protein-protein interaction databases, the team was finally able to identify three promising candidate drugs (tacrolimus, zotatifin, and nintedanib) that act on the targeted pathways.

“Our work demonstrates the power of combining transcriptomic and epigenomic analyses to identify biological factors that influence the evolution of COVID-19 hospitalization and the survival of patients with severe disease,” says Erwin Schurr, PhD, a scientist in the Infectious Diseases and Immunity in Global Health Program at the RI-MUHC and Professor at McGill’s Department of Medicine, and co-senior author. ”We are looking forward to clinical trials that hopefully will confirm the efficacy of the three drugs to reduce mortality of severely ill COVID-19 patients.”

About the study

The study A systems biology approach identifies candidate drugs to reduce mortality in severely ill patients with COVID-19 was conducted by Vinicius M. Fava, Mathieu Bourgey, Pubudu M. Nawarathna, Marianna Orlova, Pauline Cassart, Donald C. Vinh, Matthew Pellan Cheng, Guillaume Bourque, Erwin Schurr and David Langlais.

DOI: 10.1126/sciadv.abm2510

Funding for this study was provided by the Canadian Institutes of Health Research (CIHR) and the McGill University Interdisciplinary Infection and Immunity Initiative (MI4), thanks to the generosity of multiple donors to the MUHC Foundation COVID-19 Emergency Fund.

The researchers are grateful to the patients who have participated in this study.

Media contacts

Fabienne Landry
Communications coordinator, Research, MUHC
[email protected]
 

Cynthia Lee

Media Relations, Université McGill / McGill University

[email protected]

514-398-6754

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NASA will launch the CAPSTONE mission on Monday, June 27 – electriccitymagazine.ca

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Rocket Lab's Electron rocket sits atop the launch pad at Launch Complex 1 in New Zealand for a rehearsal before the CAPSTONE launch.

A small satellite is preparing to pave the way for something much greater: a fully grown lunar space station. NASA’s CAPSTONE satellite is scheduled to launch on Monday and then travel to a unique lunar orbit on the Pathfinder mission Artemis programwhich seeks to return humans to the moon later this decade.

capstone He rides aboard Rocket Lab’s Electron rocket, which will take off from the private company’s Launch Complex 1 in Mahia, New Zealand. Rocket Lab made headlines in May using a helicopter to catch a falling booster missile. CAPSTONE is scheduled to launch at 6 AM ET on June 27 with live coverage starting an hour earlier. You can watch the event in the agency website or ApplicationOr, you can watch it on the live stream below.

NASA Live: The official broadcast of NASA TV

About a week after the CAPSTONE mission, the probe’s flight will be available through NASA Eyes on the solar system Interactive 3D visualization of data in real time.

The Cislunar Autonomous Positioning System Technology Operations and Navigation Experiment (CAPSTONE) mission will send a microwave-sized satellite into near corona orbit (NRHO) around the moon. The satellite will be the first to sail its way around this unique lunar orbit, testing it for the planned date Moon Gatea small space station intended to allow a permanent human presence on the moon.

NRHO is special in that it is where the gravitational force of the Moon and Earth interact. This orbit would theoretically keep the spacecraft in a “beautiful gravitational spot” in a near-stable orbit around the Moon, according to to NASA. Therefore NRHO is ideal because it will require less fuel than conventional orbits and will allow the proposed lunar space station to maintain a stable line of communication with Earth. But before NASA builds its gateway into this highly elliptical orbit, the space agency will use CAPSTONE — which is owned and operated by Colorado-based Advanced Space — to test its orbital models.

Artist’s concept of CAPSTONE.
GIF: NASA/Daniel Rutter

Six days after launch from Earth, the upper stage of the Electron rocket will launch the CAPSTONE satellite on its journey to the Moon. The 55-pound (25-kilogram) cube vehicle will perform the rest of the four-month solo journey. Once on the moon, CAPSTONE will test the orbital dynamics of its orbit for about six months. The satellite will also be used to test spacecraft-to-spacecraft navigation technology and unidirectional range capabilities that could eventually reduce the need for future spacecraft to communicate with mission controllers on Earth and wait for signals from other spacecraft to relay.

NASA is systematically putting together the pieces for the agency’s planned return to the Moon. The The fourth and final rehearsal for the space agency’s Space Launch System (SLS) went wellpaving the way for a possible launch in late August.

more: This small satellite linked to the moon can make a path to the lunar space station

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Astronaut view of New Zealand's North Island – Earth.com

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Today’s Image of the Day from NASA Earth Observatory features the North Island of New Zealand. The photo was captured as the International Space Station (ISS) approached the southernmost extent of its prograde 51.6 degree orbit. 

From this vantage point – and with the perfect weather conditions – astronauts can get a clear view of the North Island of New Zealand, according  to ESA.

“Looking towards the northwest, the astronaut photographer captured the mottled-green island that separates the Tasman Sea from the South Pacific Ocean. On the other side of Cook Strait, South Island peeks out from beneath the cloud cover,” reports ESA.

“Seven bays surround the North Island and define its distinctive shape. The inland landscape includes grasslands (lighter green areas), forests (darker green areas), volcanic plateaus, and mountain ranges formed from sedimentary rocks.”

Lake Taupō, located in the center of the North Island, is a crater lake inside a caldera formed by a supervolcanic eruption. The lake borders the active volcano Mount Ruapehu, which has the highest peak in New Zealand. 

“The volcanic nature of the island arises from its location on the tectonic plate boundary between the Indo-Australian and Pacific Plates,” says ESA. “This plate boundary is part of the vast Pacific Ring of Fire, and leads to significant geothermal activity and earthquakes in the region. Additional volcanoes, including Egmont Volcano (Mount Taranaki), also dot the North Island landscape.”

Image Credit: NASA Earth Observatory

By Chrissy Sexton, Earth.com Staff Writer

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Artemis 1 moon mission could launch as soon as late August – Space.com

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NASA officials have declared the Artemis 1 moon rocket’s most recent “wet dress rehearsal” a success and are hopeful the mission can get off the ground as soon as late August.

The Artemis 1 stack — a Space Launch System (SLS) rocket topped by an Orion capsule — is scheduled to roll back to the Vehicle Assembly Building (VAB) at NASA’s Kennedy Space Center (KSC) in Florida on July 1, where the massive vehicle will undergo repairs and preparations for its coming launch. 

Artemis 1, the first launch for the SLS, will send an uncrewed Orion on a roughly month-long mission around the moon. The mission has experienced several delays, and most recently the rocket’s certification to fly has been held up by incomplete fueling tests — a key part of the wet dress rehearsal, a three-day series of trials designed to gauge a new vehicle’s readiness for flight. 

Related: NASA’s Artemis 1 moon mission explained in photos 

The Artemis 1 stack first rolled from the VAB to KSC’s Pad 39B in mid-March, to prep for a wet dress rehearsal that began on April 1. But three separate attempts to fill the SLS with cryogenic propellants during that effort failed, sending the stack back to the VAB for repairs on April 25. The most recent wet dress try, which wrapped up on Monday (June 20), didn’t go perfectly, but NASA has deemed it good enough to proceed with preparations for launch.

Operators were able to fully fuel SLS for the first time, bringing the launch simulation much further along than any of the attempts in April. A leak from the core stage’s engine cooling system “umbilical” line was detected during Monday’s fueling test, but mission managers determined that the deviation didn’t pose a safety risk and continued with the simulation’s terminal count. That ended up being the right decision, Artemis 1 team members said.  

Mission operators were able to run a “mask” for the leak in the ground launch sequencer software, which permitted computers in mission control to acknowledge the malfunction without flagging it as a reason to halt the countdown, according to Phil Weber, senior technical integration manager at KSC. Weber joined other agency officials on a press call Friday (June 24) to discuss the plans for Artemis 1 now that the wet dress is in the rear view mirror.

The software mask allowed the count to continue through to the handoff from the mission control computers to the automated launch sequencer (ALS) aboard the SLS at T-33 seconds, which ultimately terminated the count at T-29 seconds. 

“[ALS] was really the prize for us for the day,” Weber said during Friday’s call. “We expected … it was going to break us out [of the countdown] because the ALS looks for that same measurement, and we don’t have the capability to mask it onboard.” 

It was unclear immediately following the recent wet dress if another one would be required, but mission team members later put that question to rest.

“At this point, we’ve determined that we have successfully completed the evaluations and required work we intended to complete for the dress rehearsal,” Tom Whitmeyer, deputy associate administrator for Common Exploration Systems at NASA headquarters, said on Friday’s call. He added that NASA teams now have the “go ahead to proceed” with preparations for Artemis 1’s launch.

Before it can be rolled back to the VAB, however, the stack will undergo further maintenance at Pad 39B, including repairs to the quick-disconnect component on the aft SLS umbilical, which was responsible for Monday’s hydrogen leak. 

There’s also one more test technicians need to perform at the pad. Hot-firing the hydraulic power units (HBUs), part of the SLS’ solid rocket boosters, was originally part of the wet dress countdown but was omitted when the countdown was aborted. Those tests will be completed by Saturday (June 25), according to Lanham. Following the hot-fire tests, operators will then spend the weekend offloading the HBUs’ hydrazine fuel.

Once back in the VAB, NASA officials estimate it’ll take six to eight weeks of work to get Artemis 1 ready to roll back to Pad 39B for an actual liftoff. Cliff Lanham, senior vehicle operations manager at KSC, outlined some of the planned maintenance on Friday’s call. 

Related: NASA’s Artemis program of lunar exploration

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Among other tasks, technicians will perform standard vehicle inspections, hydrogen leak repairs, “late-stow” for the payloads flying on Orion, and software loads to the SLS core stage and upper stage. They will also install flight batteries.

“Ultimately, we want to get to our flight termination system testing,” Lanham said. “Once that’s complete, we’ll be able to perform our final inspections in all the volumes of the vehicle and do our closeouts.”

After that work is complete, the Artemis 1 stack will roll out from the VAB once again, making the eight to 11-hour crawl back to Pad 39B on July 1. Whitmeyer said on Friday that the late-August launch window for Artemis 1, which opens on Aug. 23 and lasts for one week, is “still on the table.”

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