Scientists have corrected gene mutations in mice causing an ultra-rare disease by editing DNA directly in the brain with a single injection, a feat with profound implications for patients with neurological diseases.
In tests that also included patient derived cells, the cutting-edge technique not only fixed mutations causing alternating hemiplegia in childhood (AHC) — it also reduced symptoms and extended survival in mice that had AHC and were otherwise at risk of sudden death.
The research, led by the Rare Disease Translational Center (RDTC) at The Jackson Laboratory (JAX), the Broad Institute, and the nonprofit RARE Hope, was years in the making and follows the first successful gene-editing treatment for a rare liver disease. It offers a powerful glimpse into the potential of personalized gene-editing for neurological conditions.
The findings were published today in Cell.
"Five years ago, people would have thought that going into the brain of a living organism and correcting DNA was science fiction. Today, we know this is doable," said Markus Terrey, a JAX neuroscientist who co-led the work. "Doing this directly in the brain of a living organism is scientifically fascinating. You can go into the brain, fix the mutation, and have the cells corrected for the rest of their life."
A breakthrough in gene editing
AHC typically begins during infancy and causes sudden episodes of paralysis that can last minutes or even days. These episodes may be accompanied by dystonia (muscle stiffness), eye movement issues, and developmental delays. Seizures are a significant and life-threatening component of the disease, which currently has no cure. While existing treatments aid with symptom management, they have limited effectiveness.
The scientists targeted the two most common mutations that cause AHC, known as D801N and E815K, in a gene called ATP1A3. They relied on new mouse models developed by Terrey and Cathleen (Cat) Lutz, vice president of the RDTC. Previous efforts at replicating these mutations in mice resulted in defects like those observed in AHC in humans, with mice perishing prematurely and spontaneously.
The research also has important implications for other rare genetic diseases that have long been considered incurable and have been neglected because of their complexity and rarity, Lutz said. "The idea of correcting mutations of rare diseases before someone ever develops symptoms is compelling, but it requires the development of technologies to do just that," Lutz said. "With partners and experts in the field, we develop and test these technologies for devastating diseases with very clear, early symptoms like AHC."
RARE Hope (formerly Hope for Annabel), a nonprofit advancing AHC research and developing scalable cross-disease platforms, has been a longstanding and vital partner in the project. The organization helped integrate patient priorities into the research and connected scientists at JAX and the Broad Institute with an international network of AHC experts and families. RARE Hope ensured that experimental design, endpoint selection, and data interpretation all reflected patient perspectives—insights that were crucial in designing and validating tools to correct ATP1A3 mutations.
"While the incidence of this disease is very rare, the incidence of monogenic, rare conditions that could be addressed with gene editing is actually a really big number. The impact of this success resonates far beyond AHC," said Nina Frost, founder and president of RARE Hope, a co-author of the study, and mother of a daughter with AHC. "Up until this point, we didn't know if this was a disease that could be rescued postnatally. To see data that showed not just molecular correction in cells, but a functional rescue in mouse behavior, was an incredibly exciting moment."
The team tested two next-generation techniques to correct mutations in genetically modified AHC mice. Prime editing, a technique that edits DNA letters, proved to be far more applicable than another approach called gene therapy, a more widely used therapeutic approach where healthy copies of an otherwise faulty gene are added. Prime editing corrected up to 85% of the faulty gene mutations in brain cells, restoring normal protein function, improving motor skills, reducing seizure-like episodes, and extending lifespan in mice.
"We're not working with a patient at this point, but to have this kind of demonstration in a mouse with this level of correction is a pretty big deal," Terrey said. "If we can do it for one gene variant—and we already have five in the paper—we can reasonably assume that we can do this for other variants as well. We can expand this work towards other rare diseases, because 80% of them are genetic. We know exactly where the problem is."
The treatments were delivered through a single injection into the brain. They consisted of a harmless virus called AAV9 that is commonly used as a delivery vehicle in CRISPR-based gene editing, which scientists use to make precise changes to DNA. This was done shortly after birth, allowing gene editing tools to reach a large number of neurons early in life. Additionally, the team found minimal off-target effects in patient-derived cells, suggesting the approach could be both effective and safe.
Toward personalized genetic therapies
The success of the approach is a milestone that contributes to the momentum gene editing and gene therapy approaches are gaining, such as the recent breakthrough of the first gene editing treatment that healed an infant with a rare genetic liver disorder called CPS1 deficiency in May. Now, the ability to edit DNA directly in the brain offers promising new implications for neurological diseases, the scientists said.
"A lot of these delivery approaches for gene editing are viruses or nanoparticles that are relatively easily soaked up by the liver and peripheral organs, but getting across the blood brain barrier, which has this very complex set of endothelial cells that, for very good reasons, keep viruses away from the brain, is completely different," Lutz said. "This level of editing efficiency in the brain is really quite remarkable."
As the lead investigator of the NIH Somatic Cell Genome Editing Consortium, Lutz has been a longtime collaborator with David Liu, a Core Member of the Broad Institute and co-senior author of the study who developed prime editing in 2019. By leading efforts that go beyond preclinical models, the consortium is helping position genome editing as a viable therapeutic platform, with the latest research being just one example of the powerful outcomes made possible through that collaboration, she said.
"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," Liu said. "It opens the door to one day repairing the underlying genetic causes of many neurological disorders that have long been considered untreatable."
The team is now working to test the period that provides the safest and most effective results after gene editing to reverse, rather than prevent, AHC in mice.
"We haven't necessarily reversed the disease, but we've shown we can ameliorate symptoms when treatment was given very early on when the animals were born," Lutz said. "The money shot, which we're working on now, is testing whether we can treat the disease after symptoms appear—when the mice are already showing signs like dystonia and epilepsy. If we can show benefit then, that's a whole new level. That would be a major step forward."
