Prime Editing Breakthrough Offers New Hope for AHC Community, Including Patients with G947R Variant
In a historic advance for the Alternating Hemiplegia of Childhood (AHC) community, a patient-driven nonprofit, RARE Hope, has led a groundbreaking collaboration that achieved the first successful use of prime editing to rescue a neurological disease in vivo. Working in partnership with Dr. David Liu’s laboratory at the Broad Institute and the team of Dr. Cat Lutz, VP of The Rare Disease Translational Center (RDTC) at The Jackson Laboratory, RARE Hope helped launch and shape a study that corrected disease-causing mutations in cells derived from patients with AHC and two mouse models of AHC, offering a transformative proof of concept for genetic brain disease treatment.
In this new study, published in Cell, researchers simultaneously corrected five ATP1A3 mutations associated with AHC – an ambitious scope rarely attempted in therapeutic gene editing. These mutations impair function of a critical brain protein, ATP1A3, causing episodes of paralysis, seizures, cognitive delays, and a high risk of early death. The team used prime editing, a precise “search-and-replace” gene editing tool, to edit these mutations in patient-derived cells, successfully correcting pathogenic ATP1A3 variants that account for over 65% of AHC cases, including the three most common: D801N, E815K, and G947R. They then modeled two similar Atp1a3 mutations (D801N and E815K) in mice and found that in vivo gene editing efficiently corrected these mutations, restored ATP1A3 protein function, reversed multiple behavioral deficits, and significantly extended lifespan in treated animals.
Hope 4 Livi—a nonprofit dedicated to patients with the G947R mutation—celebrates this milestone as a foundational leap toward therapies for all AHC variants and plans to support Liu Lab team on future directions for this project.
“We developed a robust framework to correct multiple mutations in parallel,” said Alexander Sousa, a postdoctoral fellow in the Liu lab and one of three co-first authors along with Holt Sakai of the Liu lab and Markus Terrey of The Jackson Laboratory.
Hope 4 Livi is now working with The Jackson Laboratory (JAX) to develop a G947R-specific “humanized” mouse model, an essential tool to extend the gene editing successes seen in this study to their variant of focus. This preclinical model will allow researchers to explore whether the same therapeutic approach can be applied to G947R, bringing precision medicine closer to a reality for even the rarest patients.
“We believe this mouse model will serve as the foundation for future breakthroughs,” said the Hope 4 Livi team. “Thanks to the framework laid out by this study, we can now pursue targets for G947R with real optimism.”
This effort represents a landmark in patient-centered research. RARE Hope, founded by Nina and Simon Frost after their daughter Annabel’s AHC diagnosis, initiated the collaboration in 2021 by engaging Liu’s team and aligning it with insights from patients and clinicians. Their approach integrated patient-reported symptom data directly into study design, prioritizing outcomes most meaningful to the AHC community like reducing paroxysmal events and improving survival.
Hope 4 Livi has worked in close alignment with RARE Hope, Cure AHC, and the Alternating Hemiplegia of Childhood Foundation to ensure that research in this field remains inclusive and responsive to the full genetic spectrum of AHC.
“This isn’t just a scientific success; it’s a blueprint,” said Hope 4 Livi. “It’s a new way to do rare disease research with patients at the center.”
About
Hope 4 Livi Hope 4 Livi was founded to accelerate research and therapeutic development for children affected by the rare G947R mutation of AHC. Working with leading scientific institutions like The Jackson Laboratory and mission-aligned organizations like RARE Hope, Hope 4 Livi is advancing scalable, patient-driven solutions for rare neurological disease.
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Support and Acknowledgments
This work was made possible through the support of the National Institutes of Health, the Chan Zuckerberg Initiative, RARE Hope, Cure AHC, the Alternating Hemiplegia of Childhood Foundation, the For Henry AHC Foundation, the Davis Family Foundation, the Toolbox Foundation L2C Initiative, the Howard Hughes Medical Institute, and the National Science Foundation. Hope 4 Livi is proud to collaborate with these partners in the pursuit of inclusive, precision-based cures for all AHC patients.
[Adapted from Rare Hope press release]