Researchers Use Genetics To Identify Potential Drugs for Early Treatment of COVID-19

Dr. Juan P. Casas, a physician epidemiologist, led the study, which called for priority to be given to clinical trials of drugs targeting two proteins. Credit: Frank Curran

A new human genetics study suggests researchers should prioritize clinical trials of drugs targeting two proteins to treat COVID-19 at an early stage.

The findings are published in the journal Nature Medicine.

Based on their analyzes, the researchers argue for prioritization of clinical trials with drugs targeting the proteins IFNAR2 and ACE2. The goal is to identify existing drugs, either FDA-approved or in clinical development for other conditions, that can be reused for the early treatment of COVID-19. By doing this, they say, people with the virus cannot be hospitalized.

IFNAR2 is the target for approved drugs commonly used by patients with recurrent central nervous system multiple sclerosis. The researchers believe the most promising ACE2 therapy against COVID-19 is a drug that was developed before the pandemic began and has been evaluated in clinical trials to reduce the inflammatory response in patients with severe respiratory disorders.

Dr. Juan P. Casas, a physician epidemiologist with the Veterans Affairs Boston Healthcare System, led the study. The research included staff from Cambridge University and the European Bioinformatics Institute in England, and Istituto Italiano di Tecnologia in Italy.

“When we started this project early last summer, most of the COVID-19 studies were done on hospital patients,” explains Casas. “Very few treatments have been tested to give to patients early in the natural history of the disease. However, as the availability of tests against coronavirus increased, there was an opportunity to identify and treat COVID-19 patients before progressing to more serious forms requiring hospitalization.

“The problem we were trying to overcome,” he adds, “is how to determine whether existing drugs, either approved or in clinical development for other conditions, can be reused for the early treatment of COVID-19. strategies for drug repurposing are based on preclinical studies, such as experiments in cells or animal models, but these types of studies may have reproducibility problems or difficulties in translating their findings to humans, usually leading to higher failure rates in clinical trials. “

Casas and his team used genetics as a starting point to identify drugs that can be reused for the treatment of COVID-19. Large-scale human genetic studies have been widely used to inform drug development programs, with some research identifying the targets of COVID-19 drugs.

“The reason we used human genetics is this,” said Casas, who is also a faculty member at Harvard Medical School. “Given that more than 90% of drugs target a human protein encoded by a gene, there is the possibility of using genetic variants within those drug genes as tools to anticipate the effects of drugs on the same protein. targeted. In other words, genetic studies that used variants within drugable genes can be understood as natural randomized studies. “

To put things in perspective, he refers to a gene encoding a protein called PCSK9. The protein is the target of a class of drugs called PCSK9 inhibitors, which are used to lower cholesterol and prevent cardiovascular disease. Researchers discovered that class of drugs because of studies showing that people who carry a particular variant within the PCSK9 gene generally have high cholesterol and are at greater risk for cardiovascular disease.

“That kind of genetic study was crucial to identify the PSCK9 protein as a target for drug discovery,” says Casas. “Drug targets with human genetic support are known to have at least twice the chance of success compared to targets without human genetic support.”

Building on these known benefits of human genetics for drug discovery, Casas and his team set out to identify all of the genes encoding proteins that were targeted for FDA-approved drugs or drugs in clinical development. They called this set of 1,263 genes the “useful drug genome.” The genes came from two large genetic datasets of more than 7,500 enrolled 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 identify the drugs most likely to prevent severe cases of COVID-19 that require hospitalization.

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

“This study goes to the heart of why we built MVP,” said Dr. Sumitra Muralidhar, director of the Million Veteran Program. “It shows the potential of MVP to discover new treatments, in this case for COVID-19.”

ACE2 is highly relevant to COVID-19 because 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. There is positive evidence from small clinical studies of the effectiveness of APN01 in COVID-19 patients, especially those hospitalized. “So, if our genetic findings are correct, this strategy should be tested in clinical trials in outpatient COVID-19 patients,” says Casas.

The IFNAR2 protein serves as the target for a family of drugs known as type I interferons, one of which is interferon beta. The drug is approved for the treatment of patients with degenerative multiple sclerosis, a chronic disease that affects the central nervous system and disrupts the flow of information within the brain and between the brain and the body. The researchers showed that people with a certain variant of IFNAR2 due to COVID-19 were less likely to be hospitalized than people without the variant.

Casas is currently planning an early clinical trial to test the efficiency and safety of interferon beta in outpatient COVID-19 patients in VA. If his genetic findings are confirmed by a trial, he says the goal would be to prescribe the drug after people are diagnosed with COVID-19, but before their condition requires hospitalization.

Casas sees a continuing need for drugs to treat people in the early stage of COVID-19, despite ongoing global vaccination campaigns.

“This is largely due to two reasons,” he says. “First, it will take time to achieve the high vaccination coverage needed to create immunity for the herd. In addition, certain coronavirus variants are emerging that appear to lead to reduced vaccine efficiency. We are not clear yet. “

Reference: “Useful Medicinal Genome-Wide Mendelian Randomization Identifies Repurposing Potential for COVID-19” by Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrícia Bento, Inigo Barrio-Hernandez, Lars Rönnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann , Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O’Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas and VA Million Veteran Program COVID-19 Science Initiative, Apr 9, 2021, Nature Medicine.
DOI: 10.1038 / s41591-021-01310-z