Prime editing corrects a childhood genetic disease in mice

Alternating hemiplegia of childhood (AHC) is a rare, one-in-a-million genetic disease that affects kids. Most cases are caused by mutations in the ATP1A3 gene. That gene makes an ATPase enzyme that is expressed in neurons. Kids with a nonfunctional version of ATP1A3 tend to experience partial paralysis and seizures, leading to significantly reduced quality of life for them and their families. A few treatments exist that help manage symptoms, but there is no cure.

Now research published in Cell provides some hope for a permanent fix (2025, DOI: 10.1016/j.cell.2025.06.038). The study comes from the lab of David Liu, a chemical biologist at the Broad Institute of MIT and Harvard, Harvard University, and the Howard Hughes Medical Institute. Liu, who has developed base-editing and prime-editing technologies, has taken it on himself to look for ways to fix several rare and debilitating genetic diseases—AHC is just the latest on his list.

In the new study, Liu and collaborators demonstrate that prime editing in human cell culture can efficiently correct four of the most common mutations in the ATP1A3 gene, along with a fifth, less common mutation in that gene. Then, by placing the prime editor in AAV9, an adeno-associated virus vector that targets neurons, the researchers were able to correct two of those ATP1A3 mutations in mice with AHC, significantly improving symptoms and survival rate. “We saw very good editing in the hippocampus. And even if you just take the bulk brain cortex, we were still seeing about 50% correction,” Liu says. “Those levels of correction for in vivo brain prime editing are, to my knowledge, unprecedented.”

The drug candidate isn’t quite ready for humans. Liu says the team has one more round of optimization to do in cell and animal studies and adds that the team is working with Rare Hope, an AHC patient advocacy organization, and potential manufacturers to bring this technology into clinical trials. “Nobody knows for sure until you actually get the clinical data, but this study gives us great hope that correcting the root cause of this disease in a onetime treatment can ameliorate many of the most devastating symptoms of AHC,” Liu says.