How he spoke Wei Zhao presented an eye-catching idea to an audience of virologists from China, Australia and Singapore at the Pandemic Research Alliance symposium in October.
Crispr’s gene editing technology is best known for delivering breakthrough novel therapies for infrequent diseases, modifying or deleting false genes in a variety of conditions: sickle cell anemia Down haemophilia. However, Zhao and his colleagues at the Institute of Infection and Immunity Peter Doherty in Melbourne came up with a novel application.
They believe Crispr could be adapted to develop a next-generation flu drug, whether it’s the seasonal strains that plague both the Northern and Southern Hemispheres every year, or worrisome novel flu variants in birds and other wildlife that could trigger another pandemic.
Crispr can edit the genetic code – the biological instructions that enable life – in the cells of any living thing. This means that it can take many forms. The most well-known version is mediated by the enzyme Cas9; this can fix errors or mutations in genes by cutting the DNA strands. But virologists like Zhao are more interested in Cas9’s lesser-known cousin, the Cas13 enzyme, which can do the same thing with RNA. In human cells, RNA molecules carry instructions from DNA for producing proteins, but the genetic code of the influenza virus consists only of RNA strands – Cas13 can exploit this gap.
“Cas13 can attack these RNA viruses and inactivate them,” Zhao explained.
Human cells do not naturally produce either Cas9 or Cas13; both of these enzymes are found in immune systems bacteria and microscopic organisms called archaea, where Cas13 enables them to disable attacking viruses called phages. Zhao and a broader team of scientists are developing an pioneering system that will provide the same benefits to humans.
Initially pioneer in the laboratory as a novel antiviral drug for Covid, the idea is to develop a nasal spray or injection that uses lipid nanoparticles to deliver molecular instructions to flu-infected cells in the respiratory tract. It’s a two-step process. The first molecule would be mRNA, which instructs cells to make Cas13, and the second would be a so-called guide RNA, which directs Cas13 to a specific part of the flu virus’s RNA code.
“Cas13 then cuts through the viral RNA, disrupting the virus’s ability to replicate and effectively stopping the infection at the genetic level,” says Sharon Lewin, an infectious diseases physician at the Peter Doherty Institute who leads the project.
While the primary goal would be to employ the technology to reduce short-term infections, Zhao also envisions the spray being used to prevent infections, such as during a particularly virulent flu season. “You would essentially be priming the cells in the airway to produce Cas13 as the first layer of defense,” he says. “It’s like an army – soldiers are armed and ready to meet the enemy.”