# Development and Validation of a Transgenic Rabbit Model of Dravet Syndrome

> **NIH NIH R61** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $354,129

## Abstract

ABSTRACT
Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. SUDEP
mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and
cardiac arrhythmias. Our work in mice led to the hypothesis that cardiac arrhythmias contribute to the mechanism
of SUDEP in channelopathy-linked genetic epilepsies. We demonstrated altered cardiac myocyte (CM) ionic
currents, calcium handling, and action potentials (APs), as well as cardiac arrhythmias in mouse models of
SCN1A-, SCN8A-, and SCN1B-linked developmental and epileptic encephalopathy (DEE). We showed that
induced pluripotent stem cell (iPSC)-derived CMs from Dravet syndrome (DS) patients have substrates for
arrhythmias. Importantly, no animal or iPSC model can completely replicate the human DS phenotype. Because
mouse and human cardiac APs are very different, we used human iPSC-CM models to investigate cell
autonomous effects of SCN1A haploinsufficiency. However, cells in 2-dimensional culture cannot replicate
complex cardiac tissues, cardiovascular changes, or cardiac innervation. Here, we will develop and validate a
large animal model in which the role of cardiac arrhythmias, in addition to seizures, in SUDEP can be
investigated. Rabbits closely replicate the human cardiac AP and provide a complete organism to translate to
the clinical setting. Our objective is to develop and validate a transgenic rabbit model of SCN1A-linked DS. We
generated a New Zealand White (NZW) rabbit Scn1a deletion model using CRISPR-Cas9 gene editing.
However, NZW Scn1a+/- rabbits showed neither seizures nor cardiac arrhythmia. We later found that F1: NZW x
Dutch Belted Scn1a+/- rabbits have seizures, cardiac arrhythmia, and premature death. These exciting results
suggest that we may have generated the first transgenic large animal model of a DEE, although this model must
now be rigorously validated. If validated, this work will be a significant advance over currently available DS
models. R61 Phase Specific Aims: 1. To characterize seizure onset, seizure types, seizure frequency and
duration, and determine the rate of SUDEP in DS rabbits. 2. To characterize arrhythmia types, frequency, and
duration, whether arrhythmias occur independently of seizures, and whether cardiac arrhythmia is associated
with SUDEP in DS rabbits. R33 Phase Specific Aim: To validate the model using the ASO drug STK-001 or the
drug combination stiripentol + clobazam to reduce seizures and SUDEP. Establishing a genetic rabbit model of
DS will better inform the translatability of neuro-cardiac mechanisms of SUDEP to human disease.

## Key facts

- **NIH application ID:** 10764816
- **Project number:** 5R61NS130070-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lori L. Isom
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,129
- **Award type:** 5
- **Project period:** 2023-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764816

## Citation

> US National Institutes of Health, RePORTER application 10764816, Development and Validation of a Transgenic Rabbit Model of Dravet Syndrome (5R61NS130070-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10764816. Licensed CC0.

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