Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates

Annie Tanenhaus, Timothy Stowe, Andrew Young, John McLaughlin, Rangoli Aeran, I. Winnie Lin, Jianmin Li, Raghavendra Hosur, Ming Chen, Jennifer Leedy, Tiffany Chou, Sirika Pillay, Maria Candida Vila, Jennifer A. Kearney, Martin Moorhead, Archana Belle, Stephanie Tagliatela*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the SCN1A gene. SCN1A encodes for the alpha subunit of the voltage-gated type I sodium channel (NaV1.1), the primary voltage-gated sodium channel responsible for generation of action potentials in GABAergic inhibitory interneurons. In these studies, we tested the efficacy of an adeno-associated virus serotype 9 (AAV9) SCN1A gene regulation therapy, AAV9-REGABA-eTFSCN1A, designed to target transgene expression to GABAergic inhibitory neurons and reduce off-target expression within excitatory cells, in the Scn1a+/- mouse model of DS. Biodistribution and preliminary safety were evaluated in nonhuman primates (NHPs). AAV9-REGABA-eTFSCN1A was engineered to upregulate SCN1A expression levels within GABAergic inhibitory interneurons to correct the underlying haploinsufficiency and circuit dysfunction. A single bilateral intracerebroventricular (ICV) injection of AAV9-REGABA-eTFSCN1A in Scn1a+/- postnatal day 1 mice led to increased SCN1A mRNA transcripts, specifically within GABAergic inhibitory interneurons, and NaV1.1 protein levels in the brain. This was associated with a significant decrease in the occurrence of spontaneous and hyperthermia-induced seizures, and prolonged survival for over a year. In NHPs, delivery of AAV9-REGABA-eTFSCN1A by unilateral ICV injection led to widespread vector biodistribution and transgene expression throughout the brain, including key structures involved in epilepsy and cognitive behaviors, such as hippocampus and cortex. AAV9-REGABA-eTFSCN1A was well tolerated, with no adverse events during administration, no detectable changes in clinical observations, no adverse findings in histopathology, and no dorsal root ganglion-related toxicity. Our results support the clinical development of AAV9-REGABA-eTFSCN1A (ETX101) as an effective and targeted disease-modifying approach to SCN1A+ DS.

Original languageEnglish (US)
Pages (from-to)579-597
Number of pages19
JournalHuman Gene Therapy
Volume33
Issue number11-12
DOIs
StatePublished - Jun 1 2022

Keywords

  • Channelopathy
  • Dravet syndrome
  • Encephalopathy
  • Gene regulation therapy
  • Preclinical models
  • SCN1A

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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