Nematode Model Opens Drug Screening Path for Rare Neurogenetic Disorder

A new disease model developed at Brown University could accelerate research into a rare neurogenetic disorder that causes paralysis in children and worsens with age. The genetically engineered C. elegans nematode, created in the lab of neuroscientist Anne Hart, offers a fast, inexpensive way to evaluate potential drug treatments for alternating hemiplegia of childhood, or AHC—a disease that currently has no cure or effective treatments.

"Humans and C. elegans nematodes share many of the same genes, including those affected by AHC," said Hart. "Because these animals are so tiny and easy to grow, they are perfect for rapidly screening drugs to find ones that have the greatest impact on AHC symptoms." The research, led by Brown Ph.D. student Diana Wall, was published in Disease Models and Mechanisms.

AHC is caused by mutations in the ATP1A3 gene, which produces an enzyme important for nerve and muscle function. Symptoms vary widely from patient to patient. Some children experience daily episodes of paralysis lasting minutes, while others have monthly episodes lasting for days. Patients endure profound neurological symptoms, from full-body paralysis and painful muscle spasms to seizures and autonomic dysfunction.

Analysis of the new worm model revealed that disease-linked mutations actively interfere with the enzyme and helped explain why AHC can present so differently from child to child. "Each of the worm AHC models shows different defects in neuron and muscle behavior, as well as slightly different sleep/arousal problems," Wall said. "This is similar to how each patient mutation causes different problems in children who have AHC. Each mutation has a slightly different effect on how this important protein works."

Existing AHC test models based on rodents and human cells lack the most common patient variants as well as the ease and scalability of nematodes. The team is now developing methods to use the model in screening potential drug treatments for the disease.

"We're going from having very few treatment options to being able to screen thousands of compounds on not just one variant of AHC, but three variants that make up about 50% of all AHC cases," said Nina Frost, who founded the nonprofit RARE Hope, which helped fund the study.