In recent years, scientists have developed remarkable gene editing technologies. Using prime editing, their group was able to prevent a debilitating rare brain disorder in mice. This new technique targets five specific genetic mutations associated with Alternating Hemiplegia of Childhood (AHC), a life-altering disorder. Broad Member and Harvard University professor, David Liu, is the leader of the study. In a second piece, it discusses how prime editing might be able to cure genetic diseases.
Prime editing, which Liu initially created in 2019, enables accurate edits to DNA without making double-stranded breaks. The researchers wanted to overcome an array of mutations simultaneously. They left behind the traditional approaches to gene editing, which tend to be targeted one mutation at a time. Their detailed findings have the potential to inform scalable, accessible treatments. This development would provide a greater positive impact to patients with more diverse rare genetic diseases.
Groundbreaking Research Team
The research team, which includes Liu as a co-senior author and a Howard Hughes Medical Institute investigator, has made significant progress in understanding and addressing AHC. Mutations in ATP1A3 gene are responsible for the condition. So researchers are zeroing in on five mutations—four of them are the most common. This multi-faceted strategy marks an important new era in gene therapy. It aims for and repairs many mutations, all in one treatment platform.
David Liu expressed his enthusiasm for the study’s outcomes, stating, “This study is an important milestone for prime editing and one of the most exciting examples of therapeutic gene editing to come from our team.” He noted some of the past successes of prime editing while heralding its future potential to cure neurological conditions that have historically been incurable.
The comparative research team was able to research and test their strategies with cultured patient-derived cells, isolated from patients with AHC. This patient-centered approach enabled them to effectively model this unique condition and pioneer best-in-class treatment methodologies that put patients first.
A Shift in Gene Editing Paradigms
Traditionally, gene editing has focused on correcting one mutation at a time. This narrow focus has seriously hampered the effectiveness of these otherwise promising treatments for complex genetic disorders. Liu’s team has still laid down a solid framework from which to tackle bigger genetic odyssey or multiple genetic odysseys at once, even. Alexander Sousa, a postdoctoral fellow in the Liu lab, noted, “We developed a robust framework to correct multiple mutations in parallel.” This increased efficiency is a significant improvement, but perhaps more importantly, this new capability paves the way for future research focused on other rare diseases.
Beyond the significance of her case alone, it reflects a much bigger picture change in how we can approach genetic disorders thanks to advanced editing technologies. “This effort was really about creating a blueprint that could be rapidly applied to other rare diseases too,” Sousa added. That flexibility is important now, as researchers work to broaden the types of disease states that can be effectively targeted.
Cathleen Lutz, vice president of the Rare Disease Translational Center at The Jackson Laboratory, praised the research team’s findings: “This level of editing efficiency in the brain is really quite remarkable.” This kind of efficiency paves the way for prime editing to one day serve as a go-to treatment for many neurological disorders.
Impact on the Rare Disease Community
This research has very real implications to the rare disease community. Nina Frost, founder and president of RARE Hope, highlighted the collaborative nature of the study: “It’s been a privilege to collaborate on such a scientifically significant effort with a team that has kept patients at the center of proof-of-concept research.” Frost further reiterated the need to engage patients in the design of research, so that development will be driven by real-world experiences and needs.
Frost further stated, “This study is a win not just for our community but for all rare neurological conditions, and a breakthrough moment in expanding access to a broader cohort of potential patients.” As such, as treatments become increasingly individualized and adaptable, they are incredibly promising. We aim to inform and support the largest number of people impacted by rare genetic conditions.
As Liu’s research demonstrates, prime editing has the potential to treat neurological conditions. Further to note, it lays the groundwork for future clinical applications. “It shows that we can use prime editing to treat genetic brain diseases, and it lays the groundwork for translating this approach to the clinic,” said Holt Sakai of the Liu lab. That’s the feeling—the sunshine—that sums up the unbounded optimism around these advancements and their potential to truly transform lives.
