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Cas13a

CRISPR-Based Anti-Viral Therapy Could One Day Foil the Flu—and COVID-19

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Artistic rendering of CRISPR Cas13a as scissors

CRISPR gene-editing technology has tremendous potential for making non-heritable DNA changes that can treat or even cure a wide range of devastating disorders, from HIV to muscular dystrophy Now, a recent animal study shows that another CRISPR system—targeting viral RNA instead of human DNA—could work as an inhaled anti-viral therapeutic that can be preprogrammed to seek out and foil potentially almost any flu strain and many other respiratory viruses, including SARS-CoV-2, the coronavirus that causes COVID-19.

How can that be? Other CRISPR gene-editing systems rely on a sequence-specific guide RNA to direct a scissor-like, bacterial enzyme (Cas9) to just the right spot in the genome to cut out, replace, or repair disease-causing mutations. This new anti-viral CRISPR system also relies on guide RNA. But the guide instead directs a different bacterial enzyme, called Cas13a, to the right spot in the viral genome to bind and cleave viral RNA and stop viruses from replicating in lung cells.

The findings, recently published in the journal Nature Biotechnology [1], come from the lab of Philip Santangelo, Georgia Institute of Technology and Emory University, Atlanta. Earlier studies by other groups had shown the potential of Cas13 for degrading the RNA of influenza viruses in a lab dish [2,3]. In this latest work, Santangelo and colleagues turned to mice and hamsters to see whether this enzyme could actually work in the lung tissue of a living animal.

What’s interesting is how Santangelo’s team did it. Rather than delivering the Cas13a protein itself to the lungs, the CRISPR system works by supplying a messenger RNA (mRNA) with the instructions to make the anti-viral Cas13a protein. This is the same idea as the Pfizer and Moderna mRNA-based COVID-19 vaccines, which temporarily direct your muscle cells to produce viral spike proteins that launch an immune response. In this case, the lung cells translate the Cas13a mRNA to produce the protein. Directed by the guide RNA that was also delivered to the same cells, Cas13a degrades the viral RNA and stops the infection. Because mRNA doesn’t enter the cell’s nucleus, it doesn’t interact with DNA and raise potential concerns about causing unwanted genetic changes.

The researchers designed guide RNAs that were specific to a shared, highly conserved portion of influenza viruses involved in replicating their genome and infecting other cells. They also designed another set directed to key portions of SARS-CoV-2.

Next, they delivered the Cas13a mRNA and guides straight to the lungs of animals using an adapted nebulizer, just like those used to deliver medicines to the lungs of people. In mice with influenza, Cas13a degraded influenza RNA in the lungs and the animals recovered without any apparent side effects. In SARS-CoV-2-infected hamsters, the same approach limited the virus’s ability to replicate in cells as the animals COVID-19-like symptoms improved.

The findings are the first to show that mRNA can be used to express the Cas13a protein in living lung tissue, not just in cells in a dish. It’s also the first to show that the bacterial Cas13a protein is effective at slowing or stopping replication of SARS-CoV-2. The latter raises hope that this CRISPR system could be quickly adapted to fight any future novel coronaviruses that develop the ability to infect humans.

The researchers report that this approach has potential to work against the vast majority—99 percent—of the flu strains that have circulated around the world over the last century. It also should be equally effective against the new and more contagious variants of SARS-CoV-2 now circulating around the globe. While more study is needed to understand the safety of such an anti-viral approach before trying it in humans, what’s clear is basic research advances like this one hold great potential for helping us to fight life-threatening respiratory viruses of the past, present, and future.

References:

[1] Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents. Blanchard EL, Vanover D, Bawage SS, Tiwari PM, Rotolo L, Beyersdorf J, Peck HE, Bruno NC, Hincapie R, Michel F, Murray J, Sadhwani H, Vanderheyden B, Finn MG, Brinton MA, Lafontaine ER, Hogan RJ, Zurla C, Santangelo PJ. Nat Biotechnol. 2021 Feb 3. [Published online ahead of print.]

[2] Programmable inhibition and detection of RNA viruses using Cas13. Freije CA, Myhrvold C, Boehm CK, Lin AE, Welch NL, Carter A, Metsky HC, Luo CY, Abudayyeh OO, Gootenberg JS, Yozwiak NL, Zhang F, Sabeti PC. Mol Cell. 2019 Dec 5;76(5):826-837.e11.

[3] Development of CRISPR as an antiviral strategy to combat SARS-CoV-2 and influenza. Abbott TR, Dhamdhere G, Liu Y, Lin X, Goudy L, Zeng L, Chemparathy A, Chmura S, Heaton NS, Debs R, Pande T, Endy D, La Russa MF, Lewis DB, Qi LS. Cell. 2020 May 14;181(4):865-876.e12.

Links:

COVID-19 Research (NIH)

Influenza (National Institute of Allergy and Infectious Diseases/NIH)

Santangelo Lab (Georgia Institute of Technology, Atlanta)