Until now, the best means of getting into a cell and delivering a drug or gene therapy has been deactivated human viruses that are able to break through the biological apparatus. A team of researchers at the Catholic University of Washington, led by biochemist Venigalla Rao, presents an alternative based on synthetic biology: a modified bacteriophage virus—which attacks only bacteria—capable of entering cells and performing tasks such as gene editing.
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Further
In a piece published this Wednesday in the magazine The nature of communicationRao’s team provides details on this type of nanoparticle, which the authors say “has the potential to transform gene therapies and personalized medicine.” The main novelty, they say, is that they are created from viruses that infect bacteria, which, among other advantages, would have a greater payload and allow us to avoid the possible memory of our immune system.
artificial vectors
The authors of the paper used a type of virus that infects bacteria called bacteriophage T4 to act as “artificial viral vectors” (AVVs). These viruses have a large internal volume and a large external surface for programming and delivery of therapeutic biomolecules. To test this, they created such viruses containing lots of proteins and nucleic acids, and in several experiments successfully introduced the complete dystrophin gene into human cells in the laboratory and performed several molecular operations to reshape the human genome.
The authors successfully introduced the complete dystrophin gene into human cells and remodeled the human genome
One of the benefits of these vehicles synthetics, their creators claim, are that they can be produced at low cost, with high yield, and the nanomaterials are reabsorbed after a while. According to them, naturally occurring human viruses such as lentiviruses used to deliver therapeutic DNA or RNA to animals have had limited delivery options and various safety issues.
Although more work is needed to assess its safety, they concluded that this alternative method based on artificial viral vectors could deliver molecules or genetic material into cells and open the possibility of treating many rare diseases with new therapies.
Viable and effective therapies
Pilar Domingo, a researcher at the Institute for Integrative Systems Biology (I2SysBio) who works with bacteriophages, believes that this is a very interesting result. “The use of phages as vehicles is not new, but it demonstrates the versatility of these viruses and opens the door to new therapies that are economically viable and highly effective,” he explained to elDiario.es. Genetically modifying phages, he says, “allows them to be able to express what we want, making the bacterial virus able to recognize a human cell and transport what we’re interested in, from antitumor to molecules that silence cellular genes.”
We are facing a platform that enables precision medicine with controlled release at the spatiotemporal level.
Pilar Domingo
— Expert on bacteriophage viruses at I2SysBio
In the specialist’s opinion, we are dealing with a biotechnological system that can help solve multiple diseases. “Until now, when you hear about nanomaterials, you usually think of chemical molecules, nanoparticles,” he says. “In this case, we use natural viruses to arbitrarily modify them based on their structure to obtain new safe and targeted therapies. We are facing a platform that enables precision medicine with controlled release at the spatiotemporal level.
“Multi-Charged Nanoparticles”
Luis Ángel Fernández, a researcher at the National Center for Biotechnology (CNB-CSIC), believes that this is a very comprehensive study in which they demonstrate the ability to transform the T4 bacteriophage virus into “authentic multi-charged nanoparticles” capable of transporting many types of biomolecules, from DNA after mRNA. “The engineering behind it is complex, but they do it thanks to a very detailed prior knowledge of this virus, which first has the ability to incorporate up to 170 kb of DNA into its capsid,” he points out. “By comparison, adenoviruses (which have been used in COVID vaccines such as the Oxford-AstraZeneca vaccine to carry the S gene of SARS-CoV-2) have the capacity to incorporate only 5 kb of DNA.”
These viral particles act as authentic Swiss Army knives, into which almost any type of gene can be added.
Luis Angel Fernandez
— CNB-CSIC researcher
The work is interesting, in his opinion, because it “shows these viral particles as authentic Swiss Army knives, to which almost any type of gene, protein or RNA (and combinations thereof) can be added to enter a human cell in a functional way.” And even “it can be a very interesting alternative in gene editing and therapy using CRISPR-Cas9”, he emphasizes.
Alfonso Jaramillo, a researcher at the Institute for Integrative Systems Biology (I2SysBio) and an expert in synthetic biology, points out that the authors have reconfigured the “head” of a large virus that infects bacteria to create a versatile platform for gene transfer. and proteins. “This invention is a breakthrough in the field of nanobiology, which combines biology with nanotechnology,” he explains.
And most interestingly, it allows the virus capsule to be used as a kind of container. “It can be filled with as many DNA molecules as you want until it’s full,” he points out. “This is different from viruses, which recognize signals in DNA to make sure they only package their own DNA.”
some limitations
Although this is an interesting advance, the authors themselves admit some limitations, such as a possible immune response against these vectors and the possibility of unintended events associated with gene editing systems. “Possible problems could be adverse reactions of the host’s immune system,” Jaramillo acknowledges. “However, this nanobiological technology remains an important step towards more effective and personalized gene and protein therapy.”
Possible problems can be adverse reactions of the host’s immune system
Alfonso Jaramillo
— Synthetic biology specialist at I2SysBio
“Undoubtedly, the limitation of the work is that it is limited to demonstration in cells in vitro culture, not in more complex tissue systems in vitro or in animals (in vivo),” adds Fernández. “What they lack is to demonstrate this with multiple cell types, particularly in mice or another in vivo model.”
“In order to draw conclusions, it is necessary to carry out further tests in vivo, which will allow us to find out whether they will be effective or whether there is a cross-immunity that inactivates the phages”, concludes Pilar Domingo. “Although much remains to be done, this area of biotechnology only opens the door to new control strategies through precision therapies.”
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