Using genetics, researchers identify potential drugs for early treatment of COVID-19
A new study using human genetics suggests researchers should prioritize clinical trials of medicine that focus on two proteins to manage COVID-19 in its early stages.
The findings appeared online within the journal Nature Medicine in March 2021.
Based on their analyses, the researchers are calling for prioritizing clinical trials of medicine targeting the proteins IFNAR2 and ACE2. The goal is to spot existing drugs, either FDA-approved or in clinical development for other conditions, which will be repurposed for the first management of COVID-19. Doing so, they say, will help keep people with the virus from being hospitalized.
IFNAR2 is that the target for approved drugs often employed by patients with relapsing sorts of the central systema nervosum disorder MS. The researchers believe the foremost promising ACE2 therapy against COVID-19 may be a drug that was developed before the pandemic began and has been evaluated in clinical trials to scale back the inflammatory response in patients with severe respiratory disorders.
Dr. Juan P. Casas, a physician epidemiologist at the Veterans Affairs Boston Healthcare System, led the study. The research included collaborators from the University of Cambridge and therefore the European Bioinformatics Institute in England, and Istituto Italiano di Tecnologia in Italy.
When we started this project early last summer, most COVID-19 trials were being done on hospitalized patients," Casas explains. "Very few treatments were being tested to offer to patients early within the explanation of the disease. However, because the availability of testing against coronavirus increased, a chance opened to spot and treat COVID-19 patients before they reach more severe forms that need hospitalization.
"The problem we tried to beat," he adds, "is the way to identify if existing drugs, either approved or in clinical development for other conditions, are often repurposed for the first management of COVID-19. most ordinarily used strategies for drug repurposing are supported pre-clinical studies, like experiments in cells or animal models. However, those sorts of studies may have problems of reproducibility or difficulties in translating their findings to humans. that sometimes results in higher rates of failure in clinical trials."
Casas and his team used genetics because the start line to spot drugs that will be repurposed for treating COVID-19. Large-scale human genetic studies are widely wont to inform drug development programs, with some research identifying COVID-19 drug targets.
"The reason we used human genetics is as follows," says Casas, who is additionally a school member at Harvard school of medicine. "Given that quite 90% of medicine target a person's protein encoded by a gene, the chance is there to use genetic variants within those druggable genes as instruments to anticipate the consequences that drugs targeting an equivalent protein will have. In other words, genetic studies that used variants within druggable genes are often conceived as natural randomized trials."
To put things into perspective, he refers to a gene that encodes a protein called PCSK9. The protein is that the target of a category of medicine called PCSK9 inhibitors, which are wont to lower cholesterol and stop disorder. Researchers discovered that class of medicine due to studies showing that folks carrying a particular variant within the PCSK9 gene tend to possess high levels of cholesterol and are at greater risk for the disorder.
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"That quite genetic study was pivotal to spot the PSCK9 protein as a target for drug discovery," Casas says. "It's known that drug targets with human genetic support have a least twice the chances of success compare to the targets without human genetic support."
Building on these known benefits of human genetics for drug discovery, Casas and his team began to spot all genes that encode proteins that served as targets for FDA-approved drugs 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 quite 7,500 hospitalized COVID-19 patients and quite 1 million COVID-free controls.
By comparing the genetic profiles of the hospitalized patients and therefore the controls, and searching at which drugs target which genes, the researchers were ready to pinpoint the drugs presumably to stop severe cases of COVID-19 that need hospitalization.
The two datasets were VA's Million Veteran Program (MVP), one among the world's largest sources for health and genetic information, and therefore the COVID-19 Host Genetics Initiative, a consortium of quite 1,000 scientists from over 50 countries working collaboratively to share data and concepts, recruit patients and disseminate findings.
"This study gets to the guts of why we built MVP," says Dr. Sumitra Muralidhar, director of the Million Veteran Program. "It demonstrates the potential of MVP to get new treatments, during this case for COVID-19."
ACE2 is very relevant to COVID-19 because the coronavirus uses that protein to enter human cells. the foremost promising ACE2 therapy against COVID-19 is that the drug APN01, which mimics the protein. The drug works by confusing the coronavirus so it attaches to the drug rather than the ACE2 protein within the human cell. Positive evidence is emerging from small clinical trials on the effectiveness of APN01 in COVID-19 patients, especially people who are hospitalized. "Hence, if our genetic findings are correct, there is a got to test this strategy in clinical trials in COVID-19 outpatients," Casas says.
The IFNAR2 protein is the target for a drug family referred to as type-I interferons, one among which is interferon beta. That drug is approved for treating patients with a degenerative sort of MS, a chronic disease that attacks the central systema nervosum and disrupts the flow of data within the brain and between the brain and therefore the body. The researchers showed that folks with a particular variant of IFNAR2 had less chance of being hospitalized thanks to COVID-19, compared to people without the variant.
Currently, Casas is early into planning a clinical test to check the efficiency and safety of interferon-beta in COVID-19 outpatients in VA. If his genetic findings are confirmed by an attempt, he says the goal would be to prescribe the drug after people are diagnosed with COVID-19 but before their conditions require hospitalization.
Casas sees a continued need for drugs to treat people within the early phase of COVID-19, despite the continued worldwide vaccination campaigns.
"This is essentially thanks to two reasons," he says. "First, it'll take a while to realize the high levels of vaccine coverage needed to make herd immunity. Also, certain coronavirus variants are emerging that appear to steer to a reduced vaccine efficiency. We aren't yet within the clear."
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