Abstracts

Rationale: The gene SCN8A encodes the voltage-gated sodium channel Nav1.6, which is localized at the axon initial segment and at nodes of Ranvier in the CNS and PNS. Exome sequencing has identified several hundred de novo mutations of SCN8A in patients with epileptic encephalopathy, a severe disorder characterized by early onset seizures, developmental delay and cognitive impairment. Many patients with SCN8A encephalopathy are nonambulatory and nonverbal, and the condition is resistant to standard anti-epileptic drugs. Most patient mutations of SCN8A result in gain-of-function changes leading to elevated channel activity and neuronal hyperactivity. Methods: To test therapeutic interventions, we generated a conditional mouse model of the patient mutation p.Arg1872Trp (Bunton-Stasyshyn, Wagnon et al., Brain 2019). We have used this model to evaluate the effectiveness of anti-sense oligonucleotides (ASOs) to compensate for neuronal hyperactivity by reducing Nav1.6 mRNA abundance. Scn8a-cond/+,E2A-CRE mice were treated by intracerebroventricular injection of an ASO that decreases the abundance of the Scn8a transcript by up to 50%. Results: We observed a dose-dependent increase in length of seizure-free survival of the mutant mice, from 2 weeks for untreated mice to 9 weeks in mice receiving two treatments of ASO. The ASO-treated mice did not exhibit side effects that can result from greater reduction of Nav1.6 function, such as muscle wasting and ataxia. Conclusions: These experiments provide pre-clinical evidence for the effectiveness of ASO therapy to treat an intractable childhood epilepsy. Reduction of neuronal excitability with SCN8A-ASO is potentially applicable to other epilepsies as well. Funding: Supported by NIH R01 NS34509