Viruses come in many forms, and Rice University bioengineer Isaac Hilton has long been fascinated by those who take control of cells without rewriting their genetic code.
“Certain non-integrating episomal DNA viruses have developed sophisticated ways of hiding inside human immune cells without altering our DNA,” said Hilton, geneticist, synthetic biologist and cell engineer. “These types of viruses can exist as circular minichromosomes that we call episomes, and some of these viral episomes can silently persist in human immune cells throughout a person’s life.”
In addition to helping viruses hide from the immune system, these circles can produce molecules that viruses use to hijack host cells and change their behavior. But as their name suggests, non-integrator episomal DNA viruses achieve their takeover without making permanent changes to the genome of their host. From an engineer’s perspective, Hilton said the ability to program immune cell behaviors and safely erase that programming when it is no longer needed or needed “makes these viruses very attractive for use. in gene and cell therapy platforms ”.
That’s why he’s teaming up with Baylor College of Medicine immunologist and infectious disease expert Dr. Andrew DiNardo to create a new technological platform for cell and gene therapy. The project is funded by a prestigious Trailblazer Award from the National Institutes of Health.
Our goal on this project is: can we hijack hijackers to safely and reversibly program medicinal functions in human cells? “
Isaac Hilton, Rice University bioengineer
“We know that these viruses can enter human cells and temporarily rewire them using genetic circuitry to balance cellular behavior for the benefit of the virus,” he said. “Reassigning these mechanisms will add valuable technologies to the toolkits for gene and cell therapy, as permanent disruptions to our genetic code can sometimes lead to unpredictable and undesirable results.”
Hilton’s team wants to show that they can co-opt some of these viral circuits to design interchangeable control elements and modules and transmit them to human immune cells in the form of synthetic circular DNA.
“We want to understand the design rules that will allow researchers to closely and safely control how extra-chromosomal DNA – that is, DNA that is not integrated into our genomes – behaves in human cells, ”Hilton said of the three-year project, which is funded by the National Institute for Biomedical Imaging and Bioengineering.
“We also want to take advantage of safe and well-established test bed systems to create detection and response modules and monitor the therapeutic functions of immune cells in response to drugs or other environmental signals,” a- he declared. “These types of systems can lay the groundwork for new ways of predictably designing human cells without disrupting natural human DNA.”
The technique builds on current gene therapies that use “tame” viruses to deliver genetic payloads to cells. Tame viruses, which are not harmful to humans initially, are also programmed to be incapable of replicating themselves. Hilton said there might be unique advantages to designing such viruses to deliver non-permanent episomal programs.
Next-generation cell therapies that offer non-permanent programming to immune cells could serve as diagnostic agents, drug factories or sentinels that protect against multiple diseases, Hilton said. These technologies will likely work better if bioengineers can find ways to deliver large genetic loads that work “orthogonally”, meaning they don’t interfere with the day-to-day functioning of the cell.
“We want to give biomedical scientists and clinicians new tools to precisely control the large therapeutic genetic payloads in human cells,” said Hilton. “The use of extra-chromosomal genetic circuitry can result in robust gene expression outputs and more predictable and secure programming of cells, which will be a big step towards harnessing cells to correct human disease.”