Influential inventions often combine existing tools in new ways. The iPhone, for example, merged the phone, the web browser, and the camera, among many other devices.
The same is now possible with gene editing. Instead of employing separate tools to edit genes and regulate their expression, these different targets can now be combined into a single tool that can simultaneously and independently address different genetic diseases in the same cell.
Fusion of gene editing and regulation
In a new article in Nature CommunicationsResearchers at the Center for Precision Engineering for Health (CPE4H) at the University of Pennsylvania School of Engineering and Applied Sciences (Penn Engineering) describe a minimal and versatile genetic perturbation technology (mvGPT).
Able to precisely edit genes, activate gene expression, and repress genes all at the same time, the technology opens new doors for the treatment of genetic diseases and research into the fundamental mechanisms of how our DNA works.
“Not all genetic diseases are caused solely by errors in the genetic code itself,” says Sherry Gao, Penn Compact Presidential Associate Professor in Chemical and Biomolecular Engineering (CBE) and in Bioengineering (BE) and senior author of the paper. “In some cases, diseases with genetic components, such as type I diabetes, are due to how much or little certain genes are expressed.”
One tool, multiple functions
In the past, addressing multiple unrelated genetic abnormalities at once (for example, editing one gene and deleting another) would have required multiple different tools. “We wanted to build a unique platform that could precisely and efficiently edit DNA, as well as up- and down-regulate gene expression,” says Tyler Daniel, a doctoral student in the Gao Lab and one of the paper’s first co-authors.
The platform works by combining an improved “Prime Editor”, capable of modifying DNA sequences, with previously invented technologies to increase and decrease gene expression. “All of these functions are orthogonal,” says Daniel. “They can occur independently of each other at the same time.”
“This level of precision for modifying DNA sequences and gene expression was not possible before,” he continues. “Each task works independently. It’s like we took a car with a faulty navigation system and fixed the error in that system while simultaneously turning up the stereo volume and turning down the air conditioning.”
The power of precision editing
The team tested mvGPT in human liver cells with a mutation that causes Wilson’s disease, successfully removing the mutation while upregulating a gene linked to the treatment of type I diabetes and suppressing another associated with transthyretin amyloidosis. In multiple tests, mvGPT accomplished all three tasks with high precision, demonstrating its ability to target multiple genetic conditions simultaneously.
Because mvGPT takes up less space than three standalone tools, the system is also easier to transport into cells. The researchers showed that mvGPT can be delivered by multiple means, including strands of mRNA and viruses used to deliver gene editing tools.
“When you have a single tool that can accomplish all of these things at the same time,” Gao says, “the process is much simpler, because there is less machinery to have to bring into the cell.”
Moving towards greater impact
Now that the technology has shown promise in human cells, researchers plan to test mvGPT in animal models and against other diseases with genetic components, including cardiovascular diseases. “The more advanced our tools are,” Gao continues, “the more we can do to treat genetic diseases.”
This study was conducted at the University of Pennsylvania School of Engineering and Applied Sciences and was supported by the National Science Foundation (CBET-2143626) and the National Institutes of Health (HL157714).
Other co-authors include first co-authors Qichen Yuan and Hongzhi Zeng of Rice University; Emmanuel C. Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M. Abramson and Boyang Zhang, also of Rice University; and Qingzhuo Liu, Yongjie Yang, and Yong Xu of Baylor College of Medicine.