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Antisense Oligonucleotide Therapy For SCN2A Gain-of-Function Epilepsies: AES 2018 Poster

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RATIONALE: 

The clinical spectrum associated with SCN2A de novo mutations includes early and late seizure onset developmental and epileptic encephalopathy (DEE) as well as autism. Patients with early seizure-onset DEE are most frequently associated with SCN2A variants that show gain of function biophysical changes that would lead to enhanced neuronal excitability. We hypothesized that reduced expression of SCN2A in such gain of function cases would be clinically beneficial. To explore this concept a mouse model harboring a recurrent human early seizure onset DEE variant (human R1882Q) was generated and showed a strong seizure phenotype as early as P1 and severe mortality with survival rarely extending beyond P22. A gapmer ASO targeting mouse Scn2a was developed to assess efficacy in this mouse model.

METHODS:

Scn2a ASO was injected into the right intracerebral ventricles of mice heterozygous for the human R1882Q mutation. Efficacy was evaluated by survival, seizure number,electroencephalography (EEG), behavioral test batteries and whole cell recording in brain slices.

RESULTS:

Scn2a R1882Q “DEE” mice display seizures as early as postnatal day 1 and die before postnatal day 30. A single ICV injection of Scn2a ASO at postnatal day 1 significantly extended the lifespan. Survival was 29% on postnatal day 21 for untreated DEE mice compared to 95% inDEE mice treated with Scn2a ASO. The therapeutic effect of Scn2a ASO treatment was long lasting, with 69% of treated DEE mice surviving up to postnatal day 80. Scn2a ASO treatment also mitigated spontaneous seizures and restored the EEG activity of the DEE mice to that of wildtype. Scn2a ASO treated DEE mice performed similarly to wild type mice across a range of locomotor and social interaction tests. Efficacy of Scn2a ASO treatment was also evident at the single neuron level. Whole cell patch clamp recording showed that excitatory neurons expressing the Scn2a R1882Q mutation are considerably more excitable than wildtype neurons.Consistent with the observed in vivo efficacy, neurons from Scn2a ASO treated DEE mice had identical action potential input-output curves to wildtype neurons suggesting that intrinsic excitability could be restored.

CONCLUSIONS:

This study demonstrates the remarkable efficacy of Scn2a down regulation in rescuing the phenotype of a Scn2a gain-of-function DEE mouse model and has laid an important foundation for clinical development.

FUNDING: RogCon Biosciences

Relationship of Electrophysiological Dysfunction and Clinical Severity in SCN2A-Related Epilepsies.

Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures.

 

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SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet.

SCN2A mutations have been identified in various encephalopathy phenotypes, ranging from benign familial neonatal-infantile seizure (BFNIS) to more severe forms of epileptic encephalopathy such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizure (EIMFS). Thus far, no particularly effective treatment is available for severe epileptic encephalopathy caused by SCN2A mutations in children.
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Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development.

Mutations in SCN2A are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by SCN2A-associated episodic ataxia (EA) with impaired speech development.

 

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Progress in Understanding and Treating SCN2A-Mediated Disorders.

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype.

 

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Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy.

SCN2A, encoding the voltage-gated sodium channel Nav1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity.

 

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**The leading authors on this paper are Florey scientists, many working directly under Steve Petrou

Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.

OBJECTIVE:

We evaluated >8500 consecutive, unselected patients with epilepsy and neurodevelopmental disorders who underwent multigene panel testing to determine the average age at molecular diagnosis and diagnostic yield of 70 genes.

METHODS:

We reviewed molecular test results for 70 genes known to cause epilepsy and neurodevelopmental disorders using next generation sequencing (NGS) and exon‐level array comparative genomic hybridization (aCGH). A positive result was defined as the presence of 1 or 2 pathogenic or likely pathogenic (P/LP) variants in a single gene, depending on the mode of inheritance of the associated disorder.

 

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