JGH research offers hope to help reduce COVID-19 suffering

Consortium pursues promise seen in boosting levels of protein ‘OAS1’

An international consortium, including scientists from the Lady Davis Institute at the Jewish General Hospital in Montreal, has teamed up with a data-based pharma-research firm to identify likely drug candidates that could be given to early diagnosis COVID-19 patients, in order to forestall serious symptoms, hospitalization, intensive care and death.

Earlier this year, a team of researchers with the JGH, the LDI, working in conjunction with the Biobanque Québécoise de la Covid-19, discovered that people who had elevated levels of the protein OAS1 experienced less severe illness and lower rates of mortality when infected with Covid.

Further study warranted

In a paper published in Nature Medicine, they suggested that small molecules capable of boosting OAS1 warranted further study for their effect in triggering the body’s immune response against the coronavirus.

“Despite efforts to vaccinate against COVID-19, the pandemic continues to take a fearsome toll around the world,” says Dr. Brent Richards, a senior investigator at the LDI’s Centre for Clinical Epidemiology, who is one of the leaders of the consortium which goes under the name CONTEST.

‘Pursuing the promise’

“Consequently, it remains critical that we develop treatments to alleviate the terrible disease burden it inflicts on individual patients and precarious health care systems. Our consortium is dedicated to pursuing the promise of OAS1 on this front,” he adds.

As part of its COVID Stimulus Program, which includes over 20 Covid-related projects (launched in March 2020 as the pandemic was starting), Toronto-based pharma-research firm Cyclica is providing its services to the CONTEST consortium on a pro bono basis.

Using artificial intelligence drug discovery platforms, Cyclica assimilates data relevant to the OAS1 protein to search for existing, but not obvious, drugs in order to identify those that hold potential to trigger its production, thereby improving the patient’s immune response to the SARS-CoV2 virus.

Efficient and economical

According to consortium researchers, this method of drug discovery has the advantage of being efficient and economical because it repurposes small molecules that have already been discovered, and are hence that much closer to clinical approval.

“Given Cyclica’s commitment to progressing research within the COVID-19 community, the collaboration with Dr. Richards is an effort we are very keen to support in hopes of continuing to advance knowledge within the coronavirus space, as well as additional virus and disease areas” says Vern De Biasi, Cyclica’s chief partnership officer.

“The protective effect of elevated OAS1 was particularly large,” adds Dr. Sirui Zhou, a post-doctoral fellow at the LDI and first author of the paper. As such, he said the team had observed a 50 per cent decrease in the odds of very severe COVID-19 per standard deviation increase in OAS1 circulating levels.

Link to Neanderthals

Research has now reached the stage where artificial intelligence (AI) can unravel the further mystery of how to activate protective immune functions that will ward off COVID-19

The researchers believe that OAS1 likely emerged in people of European ancestry through interbreeding with Neanderthals tens of thousands of years ago. Evolutionary pressure slowly increased the prevalence of this form of OAS1, such that it is now detectable in more than 30 per cent of people of European descent.

They say it is likely that this protein served as protection against earlier pandemics, and may now prove significant for reducing the suffering caused by the current COVID-19 pandemic. Researchers in Dr. Richards’ lab made the discovery by analyzing proteins detectable in peripheral blood as a potential target.

According to CONTEST researchers, the challenge lay in determining which proteins play a causal role in disease progression, since their levels may also be influenced by COVID-19 itself or other complicating factors.

Technological advances

They say recent advances in proteomic technology – which is the capacity to isolate and measure hundreds of circulating proteins all at once – combined with genetic analyses through Mendelian randomization (a method of using measured variation in genes of known function to examine causal effect) – made possible the intricate work of untangling which proteins affected COVID-19 adverse outcomes.

They say the research has now reached the stage where artificial intelligence (AI) can unravel the further mystery of how to activate protective immune functions that will ward off COVID-19.

From genetic determinants of 931 circulating proteins, Dr. Zhou found that an increase in OAS1 levels was associated with reduced COVID-19 death or ventilation, hospitalization and susceptibility in up to 14,134 COVID-19 cases and 1.2 million controls.

Consistent results

Consortium researchers say the results were consistent in multiple sensitivity analyses.

They measured OAS1 levels in 504 patients with different COVID-19 outcomes from Biobanque Québec COVID-19, and found that increased OAS1 levels in post-infection patients were associated with protection against very severe COVID-19, hospitalization, and susceptibility.

The researchers say that with global vaccination levels unlikely to result in herd immunity any time soon, and global COVID-19 case counts recently surpassing 180 million including 3.8 million deaths, research such as theirs for effective treatments is sure to remain a public health priority for a considerable amount of time to come.