A nasty virus that infects bacteria could hold the key to improving gene therapies

Gene therapies could revolutionize medicine, but getting them into people’s bodies is harder than it might seem. A new method that reuses viruses that infect bacteria could provide a solution.

Finding ways to modify the DNA in living people’s cells could help treat or prevent a number of genetic diseases. It could also help reuse their cells to hunt down cancer or produce therapeutic molecules that could treat non-genetic conditions. But while our gene-editing tools are getting more sophisticated, putting them into people’s bodies is complicated.

Today there are some gene therapies and they mainly use modified viruses, which excel at introducing their DNA into the cells of their hosts. This makes these so-called viral vectors perfect cargo carriers for the tools and genetic material needed to modify genes inside patients’ cells. But the most commonly used adeno-associated viruses (AAVs) and lentiviruses have a rather small carrying capacity, which severely limits the scope of problems they can address.

New research from the Catholic University of America has shown that a type of bacteriophage virus that infects bacteria with a much larger hold can be repurposed to deliver gene therapies. It’s also cheap to make, stable, and easy to program to do more complex missions.

Current therapy is years ahead, but this research provides a model for developing life-saving treatments and cures, said Venigalla Rao, who led the research, in a press release. What we’re researching is how a molecular surgery can safely and accurately correct a defect and generate therapeutic outcomes and day care.

In the search for a more capable delivery vehicle, researchers have turned to a phage called T4, which belongs to the family Straboviridae and infects Escherichia coli bacteria. It has a number of promising features, including a much larger capsid (the main compartment where genetic material is stored), an infectious efficiency of nearly 100%, and the ability to replicate in just 20-30 minutes.

Furthermore, the researchers have already worked out the atomic structures of the main components of phages, making the reengineering process much easier. This allowed the team to set up what it termed an assembly-line approach in which cargo molecules such as DNA, proteins and RNA were added in sequence to the empty capsid shells and also pinned to the outside. The resulting viral vector is then coated with a shell of lipid molecules, which facilitate infiltration into human cells.

In a card inside Nature communications, the researchers showed that their engineered phage could contain stretches of DNA up to 171,000 base pairs long, which is about 20 times more than the viruses used in current gene therapies can contain. To demonstrate the potential, they used this carrying capacity to transport the entire dystrophin protein gene into human cells. Mutations in this gene are responsible for the genetic disease Duchenne muscular dystrophy.

In a series of experiments, the researchers demonstrated that the viral vector could be used to perform genome editing, gene recombination, gene replacement, gene expression and gene silencing. They also showed that it could carry complex cargoes consisting of multiple stretches of DNA targeting different genes, along with various proteins and RNA sequences. The researchers say this could eventually open the door to treating complex diseases involving multiple genes such as many cancers, neurodegenerative disorders and cardiovascular disease.

While these early results are certainly promising, Jeffrey Chamberlain of the University of Washington in Seattle said New scientist that the team has yet to demonstrate that viruses can actually deliver genes into the body, rather than simply TO human cells in a petri dish. And Rao admits there’s still a lot of work to be done in moving from the lab to the clinic.

But the ability to design custom viral vectors for a wide range of applications using their assembly line is very promising. And unlike existing viral vectors, which must be grown in human cell cultures at considerable cost, the team’s new engineered phage can be grown much easier in bacteria.

It is likely that it will take many more years of research to bring these ideas to fruition, but if successful, this could greatly expand the reach of future gene therapies.

Image credit: Venigalla B. Rao; Victor Padilla-Sanchez, Andrei Fokine and Jingen Zhu. Structural model of the T4 bacteriophage artificial viral vector.

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