New study: Montreal researchers identify three drugs that could reduce mortality in severely ill COVID-19 patients - McGill University Health Centre | Canada News Media
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, 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.”
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.
NAIROBI, Kenya (AP) — The body of Ugandan Olympic athlete Rebecca Cheptegei — who died after being set on fire by her partner in Kenya — was received Friday by family and anti-femicide crusaders, ahead of her burial a day later.
Cheptegei’s family met with dozens of activists Friday who had marched to the Moi Teaching and Referral Hospital’s morgue in the western city of Eldoret while chanting anti-femicide slogans.
She is the fourth female athlete to have been killed by her partner in Kenya in yet another case of gender-based violence in recent years.
Viola Cheptoo, the founder of Tirop Angels – an organization that was formed in honor of athlete Agnes Tirop, who was stabbed to death in 2021, said stakeholders need to ensure this is the last death of an athlete due to gender-based violence.
“We are here to say that enough is enough, we are tired of burying our sisters due to GBV,” she said.
It was a somber mood at the morgue as athletes and family members viewed Cheptegei’s body which sustained 80% of burns after she was doused with gasoline by her partner Dickson Ndiema. Ndiema sustained 30% burns on his body and later succumbed.
Ndiema and Cheptegei were said to have quarreled over a piece of land that the athlete bought in Kenya, according to a report filed by the local chief.
Cheptegei competed in the women’s marathon at the Paris Olympics less than a month before the attack. She finished in 44th place.
Cheptegei’s father, Joseph, said that the body will make a brief stop at their home in the Endebess area before proceeding to Bukwo in eastern Uganda for a night vigil and burial on Saturday.
“We are in the final part of giving my daughter the last respect,” a visibly distraught Joseph said.
He told reporters last week that Ndiema was stalking and threatening Cheptegei and the family had informed police.
Four in 10 women or an estimated 41% of dating or married Kenyan women have experienced physical or sexual violence perpetrated by their current or most recent partner, according to the Kenya Demographic and Health Survey 2022.
TEL AVIV, Israel (AP) — A rare Bronze-Era jar accidentally smashed by a 4-year-old visiting a museum was back on display Wednesday after restoration experts were able to carefully piece the artifact back together.
Last month, a family from northern Israel was visiting the museum when their youngest son tipped over the jar, which smashed into pieces.
Alex Geller, the boy’s father, said his son — the youngest of three — is exceptionally curious, and that the moment he heard the crash, “please let that not be my child” was the first thought that raced through his head.
The jar has been on display at the Hecht Museum in Haifa for 35 years. It was one of the only containers of its size and from that period still complete when it was discovered.
The Bronze Age jar is one of many artifacts exhibited out in the open, part of the Hecht Museum’s vision of letting visitors explore history without glass barriers, said Inbal Rivlin, the director of the museum, which is associated with Haifa University in northern Israel.
It was likely used to hold wine or oil, and dates back to between 2200 and 1500 B.C.
Rivlin and the museum decided to turn the moment, which captured international attention, into a teaching moment, inviting the Geller family back for a special visit and hands-on activity to illustrate the restoration process.
Rivlin added that the incident provided a welcome distraction from the ongoing war in Gaza. “Well, he’s just a kid. So I think that somehow it touches the heart of the people in Israel and around the world,“ said Rivlin.
Roee Shafir, a restoration expert at the museum, said the repairs would be fairly simple, as the pieces were from a single, complete jar. Archaeologists often face the more daunting task of sifting through piles of shards from multiple objects and trying to piece them together.
Experts used 3D technology, hi-resolution videos, and special glue to painstakingly reconstruct the large jar.
Less than two weeks after it broke, the jar went back on display at the museum. The gluing process left small hairline cracks, and a few pieces are missing, but the jar’s impressive size remains.
The only noticeable difference in the exhibit was a new sign reading “please don’t touch.”
VICTORIA – The British Columbia government is partnering with a bear welfare group to reduce the number of bears being euthanized in the province.
Nicholas Scapillati, executive director of Grizzly Bear Foundation, said Monday that it comes after months-long discussions with the province on how to protect bears, with the goal to give the animals a “better and second chance at life in the wild.”
Scapillati said what’s exciting about the project is that the government is open to working with outside experts and the public.
“So, they’ll be working through Indigenous knowledge and scientific understanding, bringing in the latest techniques and training expertise from leading experts,” he said in an interview.
B.C. government data show conservation officers destroyed 603 black bears and 23 grizzly bears in 2023, while 154 black bears were killed by officers in the first six months of this year.
Scapillati said the group will publish a report with recommendations by next spring, while an independent oversight committee will be set up to review all bear encounters with conservation officers to provide advice to the government.
Environment Minister George Heyman said in a statement that they are looking for new ways to ensure conservation officers “have the trust of the communities they serve,” and the panel will make recommendations to enhance officer training and improve policies.
Lesley Fox, with the wildlife protection group The Fur-Bearers, said they’ve been calling for such a committee for decades.
“This move demonstrates the government is listening,” said Fox. “I suspect, because of the impending election, their listening skills are potentially a little sharper than they normally are.”
Fox said the partnership came from “a place of long frustration” as provincial conservation officers kill more than 500 black bears every year on average, and the public is “no longer tolerating this kind of approach.”
“I think that the conservation officer service and the B.C. government are aware they need to change, and certainly the public has been asking for it,” said Fox.
Fox said there’s a lot of optimism about the new partnership, but, as with any government, there will likely be a lot of red tape to get through.
“I think speed is going to be important, whether or not the committee has the ability to make change and make change relatively quickly without having to study an issue to death, ” said Fox.
This report by The Canadian Press was first published Sept. 9, 2024.
