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(Abst. 1.466), 2018

Antisense oligonucleotide therapy for SCN2A gain-of-function epilepsies
Authors: Steven Petrou, RogCon Biosciences; Melody Li, Florey Institute for Neuroscience and Mental Health; Nikola Jancovsk, Florey Institute for Neuroscience and Mental Health; Paymaan Jafar-najad, Ionis Pharmaceuticals; Lisseth Burbano, The Florey Institute of Neuroscience and Mental Health; Alex Nemiroff, RogCon Biosciences; Kelley Dalby, RogCon Biosciences; Snezana Maljevic, The Florey Institute of Neuroscience and Mental Health; Christopher Reid, The Florey Institute of Neuroscience and Mental Health; and Frank Rigo, Ionis Pharmaceuticals
Content: Rationale: The clinical spectrum associated with SCN2A de novo mutations includes early andlate seizure onset developmental and epileptic encephalopathy (DEE) as well asautism. Patients with early seizure-onset DEE are most frequently associated with SCN2Avariants that show gain of function biophysical changes that would lead to enhanced neuronalexcitability. We hypothesised that reduced expression of SCN2A in such gain of function caseswould be clinically beneficial. To explore this concept a mouse model harbouring a recurrenthuman early seizure onset DEE variant (human R1882Q) was generated and showed a strongseizure phenotype as early as P1 and severe mortality with survival rarely extending beyondP22. A gapmer ASO targeting mouse Scn2a was developed to assess efficacy in this mousemodel. Methods: Scn2a ASO was injected into the right intracerebral ventricles of mice heterozygousfor the human R1882Q mutation. Efficacy was evaluated by survival, seizure number,electroencephalography (EEG), behavioural test batteries and whole cell recording in brainslices. Results: Scn2a R1882Q “DEE” mice display seizures as early as postnatal day 1 and die beforepostnatal day 30. A single ICV injection of Scn2a ASO at postnatal day 1 significantly extendedthe 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 longlasting, with 69% of treated DEE mice surviving up to postnatal day 80. Scn2a ASO treatmentalso mitigated spontaneous seizures and restored the EEG activity of the DEE mice to that ofwildtype. Scn2a ASO treated DEE mice performed similarly to wild type mice across a range oflocomotor and social interaction tests. Efficacy of Scn2a ASO treatment was also evident at thesingle neuron level. Whole cell patch clamp recording showed that excitatory neuronsexpressing 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 hadidentical action potential input-output curves to wildtype neurons suggesting that intrinsicexcitability could be restored. Conclusions: This study demonstrates the remarkable efficacy of Scn2a down regulation inrescuing the phenotype of a Scn2a gain-of-function DEE mouse model and has laid an importantfoundation for clinical development. Funding: RogCon Biosciences