Innovative Mouse Models for Ultra-Rare Neurological Disorder Could Accelerate Gene Therapy Development

Scientists at The Jackson Laboratory have engineered advanced mouse models that survive longer and are more stable, enabling detailed pre-clinical studies of alternating hemiplegia of childhood (AHC), a rare and often fatal neurological disorder affecting approximately one in a million children. This breakthrough allows researchers to explore how specific genetic mutations influence the disease's progression, shedding light on potential gene editing therapies.

Published in Neurobiology of Disease, the study highlights how variations in mutations within the ATP1A3 gene can cause distinct neurological symptoms. The research demonstrates differences in brain activity abnormalities, motor impairments, and seizures depending on the mutation. For example, mice with the E815K mutation exhibited severe epileptiform activity and neuroinflammation, while D801N mutants showed increased mortality and motor dysfunction. Monitoring biomarkers like neurofilament light chain in blood samples further aids in understanding disease dynamics and evaluating treatment responses.

By creating mutation-specific models, the team aims to develop targeted gene editing strategies that could correct these genetic defects. The improved models overcome previous limitations where early death in mice hampered research efforts, allowing for comprehensive behavioral and molecular assessments.

The research underscores the importance of understanding genetic diseases not just as isolated conditions but as part of broader neurological and genetic landscapes. These models also serve as a platform for testing new therapies that could potentially transform the treatment of AHC and other neurological disorders.

This work is part of JAX's Rare Disease Translational Center, emphasizing collaboration with families, research organizations, and patient foundations to accelerate the development of effective treatments. The ultimate goal is to translate these findings into therapies that can improve the quality of life for affected children and their families.

For more details, see the publication: Markus Terrey et al, 'Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice,' Neurobiology of Disease, 2025. [DOI: 10.1016/j.nbd.2025.106954]

Source: https://medicalxpress.com/news/2025-07-mouse-ultra-rare-disorder-pave.html