Whole-Genome Screen Finds Genes Needed for SARS-CoV-2 Cell Entry

By Anne Harding

November 16, 2020

NEW YORK (Reuters Health) - A study in human cells using CRISPR to identify genes for susceptibility to SARS-CoV-2 infection has found several potential therapeutic targets for COVID-19, including cholesterol biosynthesis.

Blocking this pathway with amlodipine reduced SARS-CoV-2 viral infection in cells, Dr. Benjamin R. tenOever of the Icahn School of Medicine at Mount Sinai, in New York City, and colleagues report in Cell.

"The results of this paper implicate a large number of host factors that are required for virus infection. Identification of these factors also increases potential drugs that may be effective at combating disease," Dr. tenOever told Reuters Health by email. "Amlodipine is a great example of this and the data presented suggest that cholesterol lowering drugs may be beneficial in combating COVID-19."

Dr. tenOever and his colleagues performed a CRISPR loss-of-function screen of more than 19,000 human genes to identify host factors necessary for SARS-CoV-2 infection. About 1,000 genes were enriched, and the top 50 included several gene complexes clustering in pathways including the vacuolar ATPases, retromer, Commander and Arp2/3 complexes. Most complexes were not lung-specific, but were expressed in a range of tissues.

"A consistent theme among the enriched complexes is endosome function and regulation," the authors note.

They validated the findings with several experiments using CRISPR knockout, RNA interference and small-molecule inhibitors, and found with single-cell sequencing that many of the genes enriched on the initial screen were involved in cholesterol biosynthesis.

"We are presently testing amlodipine in animal models. Results should be available by the end of November. If this works, formal clinical trials in patients will begin," Dr. tenOever said.

"We are also testing tamoxifen and ilomastat in animal models alongside amlodipine," he added. "All three of these drugs are already (U.S. Food and Drug Administration) approved and could be immediately deployed to COVID-19 patients if proven effective."

Dr. tenOever and his team are testing the drugs in a hamster model of COVID-19. "This will allow us to determine both the minimum effective dose to combat SARS-CoV-2 and the timing that the drug will need to be administered," he said.

"I think it would be great if physicians could take note whether COVID-19 patients on cholesterol lowering drugs fare better than a comparable cohort of patients," he concluded.

The study had no commercial funding, but two of the institutions involved in the research have applied for related patents.

SOURCE: https://bit.ly/2UmYzhW Cell, online October 24, 2020.

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