Scientists use genetics to recognize likely drugs for early administration of COVID-19
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- Source: Veterans Affairs Research Communications
- Date: 12 Apr,2021
A new study using human genetics indicates researchers should prioritize clinical trials of drugs that target two proteins to manage COVID-19 in its early stages.
The findings appeared online in the journal Nature Medicine at March 2021.
The purpose is to identify present drugs, either FDA-approved or in clinical development for other conditions, that can be repurposed for the early management of COVID-19. Doing this, they say, will help keep people with the virus from being hospitalized.
IFNAR2 is the goal for approved drugs frequently used by patients with relapsing forms of the central nervous system disorder multiple sclerosis. The researchers believe the most promising ACE2 therapy against COVID-19 is a drug that was developed prior to the pandemic started and continues to be evaluated in clinical trials to reduce inflammatory response in patients with acute respiratory ailments.
Dr. Juan P. Casas, a physician epidemiologist in the Veterans Affairs Boston Healthcare System, directed the study.
“When we started this project early last summer, most COVID-19 trials were being done on hospitalized patients,” Casas explains. “Very few remedies were being analyzed to give to patients early in the history of this disease. However, as the availability of testing against coronavirus increased, an opportunity opened to identify and treat COVID-19 patients before they progress to more severe forms that require hospitalization.
“The problem we attempted to conquer,” he adds,”is the way to identify if existing drugs, either approved or in clinical development for other conditions, can be repurposed for the early management of COVID-19. Most commonly used strategies for drug repurposing are based on pre-clinical studies, such as experiments in cells or animal models. However, those kinds of studies may have issues of reproducibility or problems in translating their findings to humans. That usually contributes to higher rates of failure in clinical trials.”
Casas and his team used genetics as the starting point to identify drugs that can be repurposed for treating COVID-19. Large-scale human genetic studies are widely used to inform drug development programs, with a few study identifying COVID-19 drug targets.
“The reason we used human genetics is as follows,” says Casas, who is also a faculty member at Harvard Medical School. “Given that more than 90% of drugs target an individual protein encoded by a gene, the chance is there to use genetic variations within those druggable genes as instruments to anticipate the effects that drugs targeting the same protein will have. In other words, genetic studies that used variants within druggable genes can be conceived as natural randomized trials.”
That kind of genetic study was pivotal to identify the PSCK9 protein as a target for drug discovery. It’s known that drug targets with human genetic support have a least twice the odds of success compare to the targets without human genetic support.”
Dr. Juan P. Casas, Physician Epidemiologist, Veterans Affairs Boston Healthcare System
To put things into perspective, he describes a gene that encodes a protein known as PCSK9. Researchers discovered that class of drugs because of research showing that people carrying a specific variant within the PCSK9 gene tend to have high levels of cholesterol and are at higher risk for cardiovascular disease.
Building on these known benefits of human genetics for drug discovery, Casas and his team set out to identify all genes that encode proteins that served as goals for antipsychotic medication or drugs in clinical development. They called this set of 1,263 genes the”actionable druggable genome.” The genes were from two large genetic datasets that totaled over 7,500 hospitalized COVID-19 patients and more than 1 million COVID-free controls.
By comparing the genetic profiles of the hospitalized patients and the controls, and looking at which drugs target which genes, the researchers were able to pinpoint the medication most likely to stop acute cases of COVID-19 that require hospitalization.
Both datasets were VA’s Million Veteran Program (MVP), one of the world’s largest resources for health and genetic information, and the COVID-19 Host Genetics Initiative, a consortium of more than 1,000 scientists from over 50 countries working collaboratively to share information and ideas, recruit patients, and disseminate findings.
“This study gets to the heart of why we built MVP,” states Dr. Sumitra Muralidhar, director of the Million Veteran Program. “It demonstrates the potential of MVP to discover new therapies, in this case for COVID-19.”
ACE2 is highly relevant to COVID-19 since the coronavirus uses that protein to enter human cells. The most promising ACE2 therapy against COVID-19 is the drug APN01, which mimics the protein. The drug works by confusing the coronavirus so that it attaches to the drug instead of the ACE2 protein in the human cell. Favorable evidence is emerging from small clinical trials on the effectiveness of APN01 in COVID-19 patients, especially those that are hospitalized. “Hence, if our genetic findings are correct, there’s a need to test this strategy in clinical trials in COVID-19 outpatients,” Casas says.
The IFNAR2 protein functions as the target for a drug family called type-I interferons, one of which is interferon beta. The researchers showed that individuals with a specific version of IFNAR2 had less likelihood of being hospitalized because of COVID-19, compared to people without the variant.
Presently, Casas is early into planning a clinical trial to check the efficacy and safety of interferon beta in COVID-19 outpatients in VA.. If his genetic findings are supported by a trial, he states the goal is to prescribe the drug after people are diagnosed with COVID-19 but before their conditions require hospitalization.
Casas sees a continued need for medication to treat people in the first phase of COVID-19, regardless of the continuing worldwide vaccination campaigns.
“This is largely due to two reasons,” he says. “First, it will take some time to attain the high levels of vaccine coverage needed to make herd immunity. In addition, certain coronavirus versions are emerging that seem to lead to a reduced vaccine efficiency. We are not yet in the clear.”
Gaziano, L., et al. (2021) Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nature Medicine. doi.org/10.1038/s41591-021-01310-z.