Potential gene therapy targets rare epilepsy variant

Researchers may be one step closer to developing a gene therapy for a rare form of epilepsy linked to sodium channel variants.

A recent study by a team at Michigan Medicine, University of Michigan (USA), explored a gene therapy approach to regulate sodium channel levels in the brains of mice. This proof-of-concept study could pave the way for a gene replacement therapy targeting SCN1B-linked developmental and epileptic encephalopathy (DEE52).

Dravet syndrome is a developmental and epileptic encephalopathy (DEE) that typically emerges in early childhood, leading to seizures, cognitive impairment and sometimes sudden death. Most cases of Dravet syndrome are caused by mutations in SCN1A, a gene encoding a sodium channel subunit. However, in some cases, variants in SCN1B, which encodes voltage-gated sodium channel β1 subunits, have been linked to Dravet syndrome or a more severe early infantile epilepsy known as DEE52.

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This study explored gene replacement therapy as a potential treatment for SCN1B-related DEE52, using a Scn1b-null mouse model to assess whether restoring β1 expression could reduce seizure severity and improve survival. The absence of the Scn1b gene results in reduced excitability of parvalbumin-positive interneurons (inhibitory) and pyramidal (excitatory) neurons. As a result, these neurons become less responsive to stimulation, leading to hypoexcitability that likely disrupts the neuronal signaling seen in conditions like DEE52.

The researchers assessed a gene therapy, AAV-Navβ1, which consists of an adeno-associated viral (AAV) vector encoding C-terminal epitope-tagged β1 cDNA under the control of a modified Gad1 promoter. The therapy was administered via bilateral intracerebroventricular injection to Scn1b-null mice on the second day after birth.

They observed that AAV-Navβ1 treatment increased β1 expression in both excitatory and inhibitory neurons, reduced seizure severity and duration, prolonged lifespan, decreased susceptibility to hyperthermia-induced seizures, normalized Scn1a mRNA expression and restored cortical neuron excitability. However, they found that when the mice were given the gene therapy at day 10, it was ineffective, suggesting that early postnatal intervention is crucial for therapeutic success.

The researchers noted that while the mouse model replicated the symptoms of DEE52, the mice lacked the Scn1b gene altogether, whereas patients carry a mutated form of SCN1B. Additionally, they noted that AAV-Navβ1 resulted in an overexpression of β1, which may not be suitable or safe for all SCN1B-related DEE52 patients, but they are hopeful that this development represents a significant step toward developing gene replacement therapy for SCN1B-linked DEE52.