Gene therapy for ATP1A3-Related Neurologic Disorders

Unmet Need
Alternating Hemiplegia of Childhood (AHC) is a rare neurologic disorder affecting children, causing episodes of temporary paralysis, dystonia, and severe behavioral issues, with prevalence estimates ranging from 1 in 1 million to 1 in 100,000. Approximately 80% of AHC cases result from spontaneous mutations in the ATP1A3 gene, which encodes a critical subunit of the Na+/K+ ATPase pump responsible for maintaining cellular ionic balance. Dysfunction of this pump contributes to neurological conditions beyond AHC, including epilepsy, stroke, hypoglycemia, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. As no cure exists for AHC, only symptom management, an effective therapy to target ATP1A3-related dysfunction could impact both rare and common neurological disorders.

Technology
Duke inventors have developed a gene therapy designed to rescue the Na+/K+ ATPase enzyme's function by delivering a healthy ATP1A3 gene into affected cells using an AAV9 vector. This therapy specifically targets the alpha-3 subunit of the Na+/K+ ATPase, whose dysfunction leads to AHC and other movement disorders. The AAV9 vector enables targeted expression of ATP1A3 in relevant tissues, where it has successfully demonstrated expression and efficacy in rodent models, establishing proof-of-concept as a disease-modifying approach for ATP1A3-related conditions.

Other Applications
This technology could also be used for other ATP1A3-related diseases including rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) and several other ATP1A3 mutation related disorders. Additionally, restoring ATP1A3 function may benefit conditions involving secondary ATPase dysfunction, such as epilepsy and neurodegeneration related to Alzheimer’s and Parkinson’s disease.

Advantages

• First-in-class, disease-modifying therapy for AHC and other Na+/K+ ATPase pump disorders.

• Potential for a single-dose, long-lasting treatment effect.

• Advanced development stage, with demonstrated preclinical proof-of-concept using AAV9 for targeted gene delivery.