First-in-Neuro Breakthrough: Next-Generation Genetic Editing Tool Rescues Devastating Childhood Brain Disease in vivo
Broad-JAX-RARE Hope collaboration delivers powerful proof-of-concept for gene editing in neurological disease
In a historic first for neurological disease, researchers have used prime editing––a next-generation genome editing tool––to eliminate symptoms of a devastating childhood brain disorder in a mouse model of human disease. The study, published in Cell, marks the first time prime editing has successfully rescued a neurological disease in vivo.
Researchers investigated prime editing as a treatment for Alternating Hemiplegia of Childhood (AHC), a severe pediatric disorder caused by mutations in the ATP1A3 gene. The study was led by the laboratory of Dr. David Liu of the Broad Institute, whose lab developed prime editing in 2019. Dr. Cat Lutz, a leading expert in neurogenetic mouse modeling and pre-clinical development, and VP of The Rare Disease Translational Center (RDTC) at The Jackson Laboratory co-led the effort.
Prime editing is a versatile "search-and-replace" gene editing technology that empowers researchers to precisely re-write stretches of DNA, including those responsible for disease. Because it can correct a broad range of mutations, prime editing offers the potential to correct the vast majority of disease-causing mutations.
"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," said Liu, co-senior author of the paper, Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute. "It raises the possibility of one day repairing the underlying genetic causes of many neurological disorders that have long been considered untreatable." Liu is also a Howard Hughes Medical Institute investigator and a professor at Harvard University.
Critical to the development of gene editing for AHC were the large-scale mouse studies conducted by the RDTC, allowing researchers to move from cell-based work to testing in living organisms. After a significant characterization effort across multiple mouse models of AHC, Lutz's team investigated gene replacement therapy and a gene editing study in parallel. Multiple patient-relevant phenotypes were identified – and then corrected with Liu's editors. "The technological advances around gene editing and delivery are amazing," said Lutz, who was awarded the Rare Impact Award by the National Organization for Rare Disorders in 2021 for her pre-clinical and clinical efforts in rare diseases. "In the application of these technologies, it's important that we understand, in a mammalian system that represents the disease, how much gene editing is needed and when in the course of the disease it needs to be delivered."
This pioneering effort began with a rare diagnosis – and a non profit with a bold vision: RARE Hope. Founded in 2017 by Nina and Simon Frost after their daughter Annabel was diagnosed with a rare neurological condition, RARE Hope advances research designed to scale across diseases by supporting platform therapeutics and targeting shared biological mechanisms. RARE Hope began a collaboration with Lutz in 2018, leveraging the efforts of her group as a hub across a range of therapeutics and biomarker studies. In 2021, the organization approached Liu to explore a gene editing strategy for AHC. That conversation launched a ground breaking study with implications across multiple diseases.
"While AHC is extremely rare, it represents one of thousands of monogenic diseases that could, in principle, be treated with gene editing," said Nina Frost, co-founder and president of RARE Hope, co-author of the study, and mother to a daughter living with AHC. "This is truly a breakthrough for genetic neurological conditions. The impact of this success resonates far beyond AHC."
RARE Hope played a central role throughout 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," said Frost. "This is a model for patient-relevant, patient-centered research because the team included us as true partners."
A Landmark Collaboration
Dr. Alexander Sousa and Dr. Holt Sakai, postdoctoral fellows in Liu's lab, served as co-first authors alongside Dr. Markus Terrey from Lutz's team. The collaboration brought together leading scientists in a cross-institutional effort. Dr. Al George (Northwestern University), Dr. Kathleen Sweadner (Harvard/MGH), and Dr. Natalia Morsci, RARE Hope's chief science officer, were key collaborators, contributing critical expertise across multiple disciplines. Dr. Christine Simmons in the George Lab and Dr. Elena Aristarkhova in the Sweadner Lab were also important contributors. Lutz, George, Sweadner, and Morsci all serve on RARE Hope's Scientific Advisory Board.
A Path Forward for Gene Editing in the Brain
Alternating Hemiplegia of Childhood (AHC) is caused by mutations in the ATP1A3 gene, which encodes a protein essential for normal brain function. Symptoms typically begin in infancy and include episodes of paralysis and dystonia, seizures, motor and cognitive impairment, and an elevated risk of early death. No disease modifying therapies currently exist.
Using two mouse models of AHC that faithfully recapitulate the broad phenotypic spectrum seen in patients, the study demonstrates that prime editing can not only correct ATP1A3 mutations at the DNA level, but also restore protein function, reduce multiple symptom types, and significantly extend survival across two distinct models.
"The results really exceeded our expectations," said Sakai. "This is a powerful proof of concept. 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."
"Our group's success in investigating prime editing in rare but devastating diseases like AHC validates an impactful approach that can accelerate science and the development of novel therapeutics, while simultaneously offering a path forward for patients who far too often have limited support for therapy development," said Terrey.
A Platform Approach for Genetic Intervention
The Liu team corrected five of the most common AHC-causing mutations––an ambitious technical undertaking on an unusually broad scale for therapeutic gene editing research. Their aim was not merely to target a single mutation, but to establish a generalizable platform capable of correcting multiple variants in parallel, with potential applications across other rare diseases.
"We developed a reproducible framework to correct multiple mutations in parallel," said Liu fellow Sousa. "This was about creating a blueprint that could be rapidly applied to other rare diseases too."
"RARE Hope was formed to create platform approaches to therapy development, to translate working therapies for one disease or patient into a production line of therapies for many," said RARE Hope co-founder Simon Frost. "This effort is a perfect example of our mission in action."
The Power of Patient Partnership
Nina Frost sees the project as a model for patient partnership in scientific research, with RARE Hope contributing to study design, research priorities, and data interpretation.
RARE Hope served both as a representative of the patient community and as a strategic connector––bringing together investigators, engaging international experts, and ensuring that patient perspectives shaped the research from start to finish.
"We integrated survey data from the patient population into experimental design," said Nina Frost. "Our data showed that paroxysmal symptoms were the most difficult symptom type for patients to endure. We wanted to make sure that a therapy could attenuate those symptoms in mice, because that was most relevant to patients."
By grounding decisions about endpoints, behavioral assays, and translational goals in patient-reported data, the collaboration produced a study that reflects the needs and priorities of the AHC community.
"It's a demonstration of how patient groups, when treated as full partners, can help drive rigorous, clinically meaningful science," she added.
RARE Hope scientific director Morsci agrees. "It's incredibly encouraging to see a DNA editing approach achieve phenotypic rescue in a mouse model of this ultra-rare neurological disorder," Morsci says. "It's been an honor to support the collaborative effort that helped connect patient insights with the research teams developing and testing this promising therapeutic strategy––an example of how patient-centered science can help accelerate therapy development."
"This is a win not just for our community," Nina Frost says, "but for all rare and genetic neurological conditions. And, hopefully, for many neurological patients one day."
About RARE Hope
When their daughter Annabel was diagnosed with AHC at age two, Nina and Simon Frost set out on a mission to develop therapeutics for her rare disorder. Their work quickly evolved beyond AHC. RARE Hope (formerly Hope for Annabel) is a non-profit focused on accelerating research for AHC and other rare neurological diseases and developing scalable, patient-centric research platforms to benefit the larger rare disease community.
Adapted from a Broad Institute news story
Support and Acknowledgments
This work was supported by funding from the National Institutes of Health, the Chan Zuckerberg Initiative, RARE Hope, the Alternating Hemiplegia of Childhood Foundation, the For Henry AHC Foundation, the Davis Family Foundation, the Toolbox Foundation L2C Initiative, Cure AHC, the Howard Hughes Medical Institute, and the National Science Foundation.