Gene therapy breakthrough offers hope for severe Dravet syndrome cases

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMFeb 18 2025

Researchers successfully use an adeno-associated viral vector to restore brain function in a mouse model of SCN1B-linked DEE52, reducing seizures and extending lifespan, paving the way for future gene therapy in patients.

Study: Neonatal but not Juvenile Gene Therapy Reduces Seizures and Prolongs Lifespan in SCN1B-Dravet Syndrome Mice. Image Credit: Natali _ Mis/Shutterstock.com

Developmental and epileptic encephalopathies (DEE) are a group of severe disorders characterized by frequent seizures and resulting intellectual and developmental disabilities, often with a genetic basis.

One such condition is Dravet syndrome (DS), which typically emerges within the first year of life. A recent study published in the Journal of Clinical Immunology highlights the potential benefits of neonatal gene therapy in a DS mouse model.

Introduction

DS is primarily caused by mutations in the SCN1A gene, which encodes the α subunit (Nav1.1) of the voltage-gated sodium channel (VGSC) in neuronal cell membranes. However, mutations in SCN1B can also lead to DS or a more severe form of DEE, known as early infantile DEE52.

These seizures are resistant to conventional treatments and are associated with a high risk of mortality during episodes.

The missing protein in DEE52 is the β1 subunit of the VGSC, essential for neuronal excitation and modulation of sodium ion flow through both VGSCs and voltage-gated potassium channels. This subunit plays a critical role in brain and heart development by regulating excitable properties and gene transcription.

In mice lacking Scn1b, a condition resembling DEE52 develops, characterized by spontaneous whole-body seizures, failure to thrive, ataxia, and cardiac arrhythmias. These symptoms lead to premature death within the first three weeks of life.

Research has shown that cortical neurons in these mice exhibit abnormalities, with impaired excitatory responses in both parvalbumin-positive interneurons and pyramidal neurons. Additionally, the absence of the β1 subunit leads to reduced Scn1a and Nav1.1 expression at both RNA and protein levels.

Study overview

The study aimed to develop and evaluate a gene replacement therapy for DEE52 using an adenovirus-associated virus (AAV) vector encoding circular DNA (cDNA) for the β1 subunit, termed AAV-Navβ1. This vector was administered into the cerebral ventricular spaces of Scn1b-null mice.

Following treatment, the AAV-Navβ1 vector successfully expressed the β1 subunit protein in both excitatory and inhibitory neurons. Mice treated on the second day of life experienced fewer and less severe seizures, along with a notable increase in lifespan.

Additionally, they did not exhibit seizure susceptibility to fever, a common trigger in untreated Scn1b-null mice.

Restoring the β1 subunit also reinstated Scn1a expression, improving cortical neuron excitability. However, despite the significant increase in survival, treated mice failed to gain normal weight.

While untreated pups weighed approximately 5.5 g at the time of death, treated pups reached about 10 g, still significantly below the typical 20 g weight seen in healthy mice by 40 days of age.

Variability in response

The effectiveness of AAV-Navβ1 therapy varied among treated mice. In some cases, animals continued to experience seizures, albeit fewer, shorter, and milder, with no episodes lasting more than 10 seconds.

Among a subset of 40 treated mice, most lived beyond 30 days, though three died from seizures and others succumbed to wasting. Some mice, however, survived over 100 days with no seizures, appearing normal aside from their smaller size.

Timing of treatment

Interestingly, administering double the dose of AAV-Navβ1 on the tenth day of life did not yield improvements, suggesting that irreversible brain changes may have already occurred.

Alternatively, the dose may have been insufficient as the brain grew. Previous studies indicate that certain AAV vectors take up to two weeks to reach therapeutic levels of mRNA and protein expression in the brain, which could explain the lack of effect in later treatments.

Safety in normal mice

When AAV-Navβ1 was administered to healthy mice, excessive β1 subunit expression was observed in the brain without any apparent harm. Treated pups lived beyond 100 days, and while neuronal firing patterns changed, no spontaneous epileptic activity or premature death occurred.

In Scn1b-null neurons, depolarization returned to normal, while in wild-type neurons, a hyperpolarizing shift occurred, leading to increased firing frequencies at lower thresholds. This could reflect the high levels of β1 protein expression in unaffected brains after treatment.

Conclusion

“This work lays the foundation for future development of a gene therapeutic strategy for SCN1B-linked DEE patients.” The findings demonstrate the promise of early gene therapy in extending lifespan and reducing seizure severity in a mouse model of DEE52.

Future research will be crucial in optimizing dosage, timing, and delivery methods to maximize therapeutic benefits.