Targeting AHC with AAV Prime Editing

For babies with Alternating Hemiplegia of Childhood (AHC), a rare and severe neurodevelopmental disorder, symptoms like paralysis attacks, muscle contractions, and seizures often appear months after birth. With no current treatments, patients face muscle loss, developmental delays, and cognitive impairments.

Gene Editing Breakthrough

In a significant Cell study, researchers from the Broad Institute and the Jackson Laboratory used prime editing technology to correct the genetic causes of AHC in a mouse model. This breakthrough offers hope for a one-time AHC therapy and has wider implications for other neurodevelopmental disorders. As co-author Cathleen Lutz noted, “This level of editing efficiency in the brain is really quite remarkable.”

Led by David Liu, the team targeted five mutations in the ATP1A3 gene, responsible for up to 70 percent of AHC cases.

Precision and Promise

The team focused on prime editing, a precise genetic engineering technique derived from CRISPR-Cas9 that allows for specific DNA changes without inducing harmful double-stranded breaks. After successful in vitro correction in patient-derived stem cells, they tested the approach in vivo.

They delivered the prime editing system via an FDA-approved AAV9 viral vector into the brains of postnatal mice in two AHC models. Results were highly promising: a single injection led to significant editing efficiencies (up to 85% correction) and remarkable improvements. Treated mice showed better survival, fewer and less severe attacks, and restored motor coordination, similar to healthy mice. Co-author Alexander Sousa remarked, “Now we know you can [intervene after birth].”

The authors believe this approach, with further development and less invasive delivery, could provide a much-needed therapy for AHC in humans. It also holds potential for other ATP1A3 mutations and neurodevelopmental disorders. Liu concluded, “This study is an important milestone for prime editing… It opens the door to one day repairing the underlying genetic causes of many neurological disorders that have long been considered untreatable.”