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Crispr Enables Inhaled Flu, Covid-19 Treatment

Nebulizer mask

Nebulizer mask (Marco Verch, Flickr,

5 Mar. 2021. A biomedical engineering lab designed and tested in lab animals gene-edited therapies for influenza and Covid-19, inhaled by patients with a home device. The treatment and tests using the gene-editing technique Crispr are developed by researchers from Emory University and Georgia Tech in Atlanta, and described last month in the journal Nature Biotechnology.

A team from the biomedical engineering lab of Philip Santangelo, affiliated with both institutions, is seeking faster development of treatments for infectious disease outbreaks and pandemics, of which Covid-19 is only the latest. Santangelo’s lab studies the biology of RNA-driven viruses, which make up nearly all of the viruses known to infect humans. In this study, the Emory-Georgia Tech team targets regions of viruses that remain constant from one variation to another, with a form of synthetic messenger RNA or mRNA like that used in new vaccines to prevent Covid-19 disease.

To attack viruses with mRNA, the researchers employ Crispr, short for clustered regularly interspaced short palindromic repeats. Crispr is a genome-editing process based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. Most Crispr applications edit DNA with an editing enzyme called Cas9. In this project, the team used an RNA-editing enzyme called Cas13a, which edits with multiple cuts in RNA strands. As reported by Science & Enterprise in December 2020, Cas13a is being studied for home-based Covid-19 diagnostics.

To treat respiratory diseases, the researchers attack with Crispr-Cas13a enzymes the RNA that codes for the constant parts of viruses. In this study, the team turned to colleagues at Centers for Disease Control and Prevention, also in Atlanta, for genetic sequences representing known strains of influenza and SARS-CoV-2 viruses responsible for Covid-19. Those sequences revealed the best targets in the genomes for their proposed treatments: the PB2 region in influenza that determines the virus’s virulence and the replicase gene that governs protein production in SARS-CoV-2 viruses, as well as the nucleocapsid gene that codes for the virus’s outer membrane protein.

Formulated as a breathable mist

The team designed their treatments with a similar structure, where only the Crispr RNA to guide the Cas13a enzymes is changed. “It’s really quite plug-and-play,” says Santangelo in university statement adding, “We let the biology dictate what our targets would be.”

In addition, the researchers formulate their synthetic mRNA treatments with a biocompatible polymer, poly-beta amino esters or PBAE that makes it possible to deliver the treatments as a breathable mist using a device called a nebulizer. This device has a small compressor that turns liquids into vapors and can be used at home with a mask or mouthpiece. The team built a nebulizer-like device to test its mRNA treatments with mice and hamsters.

Results of the tests show the treatment for influenza degraded the RNA in lung tissues of infected mice. And with hamsters infected with SARS-CoV-2, the treatment reduced both viral replication and symptoms. The team notes that mRNA treatments have a limited durability in the body, which enhances their safety. “The mRNA is transient,” says Santangelo. “It doesn’t get into the nucleus, doesn’t affect your DNA.”

The research was funded by a grant from a Defense Advanced Research Projects Agency, or Darpa program to create safe, effective, and easily deployable medical countermeasures for pandemics. Those requirements led to a nebulizer formulation for the proposed therapies.

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