Researchers use genetics to identify potential drugs for early management of COVID-19

New studies using human genetics suggest that researchers should prioritize clinical trials of drugs targeting two proteins in order to control COVID-19 at an early stage.

Survey results published online in the journal Nature medicine March 2021.

Based on their analysis, researchers are seeking to prioritize clinical trials of drugs that target the proteins IFNAR2 and ACE2. The goal is to identify existing drugs that are FDA-approved or in clinical development for other conditions and can be reused for early management of COVID-19. Doing so can prevent people with the virus from being hospitalized, they say.

IFNAR2 is a popular drug target for patients with multiple sclerosis with recurrent central nervous system disorders. Researchers believe that the most promising ACE2 therapy for COVID-19 is a drug that was developed before the onset of the pandemic and was evaluated in clinical trials to reduce the inflammatory response in patients with severe respiratory illness. I will.

The study was led by Dr. Juan P. Casas, a veteran Boston Healthcare System physician epidemiologist. The study included collaborators from the University of Cambridge, the European Bioinformatics Institute in the United Kingdom, and Istituto Italiano di Tecnologia in Italy.

“When we started this project early last summer, most COVID-19 trials were conducted on inpatients,” explains Casas. “There were few treatments tested to give to patients early in the natural history of the disease, but as the availability of tests for coronavirus increased, COVID-19 patients were identified before they became more severe. I have an opportunity to be treated. I need to be hospitalized.

“The problem we tried to overcome is how to identify whether existing drugs that have been approved or are in clinical development in other conditions can be reused for early management of COVID-19. It is based on preclinical studies such as experiments on strategic cells and animal models most commonly used for repositioning, although these types of studies have reproducibility problems or translate results into humans. It can be difficult to do, which usually results in a higher failure rate in clinical trials. “

Casas and his team used genetics as a starting point to identify reusable drugs for the treatment of COVID-19. Large-scale human genetic studies have been widely used to inform drug development programs, along with several studies identifying drug discovery targets for COVID-19.

“The reasons we used human genetics are as follows,” says Casas, a faculty member at Harvard Medical School. “Given that more than 90% of drugs target human proteins encoded by genes, genetic variation within those drug-discoverable genes is a means of predicting the effects of drugs targeting the same protein. In other words, studies using mutations in gene-discoverable genes can be thought of as natural randomized trials. “

To get an overview of things, he refers to a gene that encodes a protein called PCSK9. This protein is the target of a class of drugs called PCSK9 inhibitors that are used to lower cholesterol and prevent cardiovascular disease. Researchers have shown that people with certain mutants in the PCSK9 gene are more likely to have high levels of cholesterol and are at increased risk of cardiovascular disease. I found.

This type of genetic research was crucial for identifying the PSCK9 protein as a target for drug discovery. Drug targets with human genetic support are known to be at least twice as likely to succeed as targets without human genetic support. “

Dr. Juan P. Casas, Physician Epidemiologist, Veterans Boston Healthcare System

Based on these known benefits of human genetics for drug discovery, Casas and his team will identify all genes encoding proteins that serve as targets for FDA-approved drugs or drugs under clinical development. Has begun. They called this set of 1,263 genes a “practical drug-discoverable genome.” The genes were from two large genetic datasets consisting of a total of more than 7,500 inpatient COVID-19 patients and more than 1 million COVID-free controls.

By comparing gene profiles of inpatients and controls to determine which drugs target which genes, researchers are most likely to prevent severe cases of COVID-19 requiring hospitalization. I was able to identify it.

The two datasets collaborate with VA’s Million Veteran Program (MVP), one of the world’s largest sources of health and genetic information, and more than 1,000 scientists from more than 50 countries to share data. It was the COVID-19 Host Genetics Initiative, a consortium. Come up with ideas, recruit patients, and disseminate the findings.

“This study is at the heart of why we built the MVP,” says Dr. Smitramlaridal, director of the Million Veteran Program. “This shows that MVP may discover a new treatment, in this case COVID-19.”

ACE2 is highly related to COVID-19. This is because the coronavirus uses the protein to invade human cells. The most promising ACE2 therapy for COVID-19 is the protein-mimicking drug APN01. The drug works by disrupting the coronavirus, so it attaches to the drug instead of the ACE2 protein in human cells. Positive evidence emerges from small clinical trials of the efficacy of APN01 in COVID-19 patients, especially inpatients. “Therefore, if our genetic findings are correct, we need to test this strategy in clinical trials of COVID-19 outpatients,” says Casas.

The IFNAR2 protein serves as a target for a family of drugs known as type I interferon. One of them is interferon beta. The drug is approved to treat degenerative patients with multiple sclerosis, a chronic disease that attacks the central nervous system and obstructs the flow of information in and between the brain and body. Researchers have shown that people with a particular variant of IFNAR2 are less likely to be hospitalized for COVID-19 than people without the variant.

Casas is currently in the early stages of planning a clinical trial to test the efficiency and safety of interferon beta in COVID-19 outpatients in Virginia. If his genetic findings are confirmed by trials, he says the goal is to prescribe drugs after people are diagnosed with COVID-19 and before their condition requires hospitalization. I will.

Casas sees an ongoing need for drugs to treat people in the early stages of COVID-19, despite the ongoing global vaccination campaign.

“This is for two main reasons,” he says. “First, it takes time to achieve the high levels of vaccination required for production. Herd immunity.. In addition, certain coronavirus variants have emerged that appear to reduce the efficiency of the vaccine. It’s not clear yet. “