Advanced Models of Epilepsy

Developing novel therapies for genetic refractory epilepsies of childhood using mouse and organoid models

Technology Overview

Genetic epilepsies in childhood constitute a complex group of disorders, with diverse etiologies, and clinicopathologic features. Advances in genetic technology have revealed that a large portion of these disorders arise from mutations in genes that are critical for multiple neuronal functions.

Dravet syndrome, a severe, life-threatening form of epilepsy that starts in infancy and has an array of comorbidities, is caused by mutations in SCN1A, a gene for a sodium channel that is involved in the generation and propagation of electrical impulses in neurons. Leigh syndrome, a metabolic disorder due to mitochondrial dysfunction that presents with severe seizures, can result from mutations in either the nuclear or mitochondrial genomes. Leigh syndrome is usually fatal within the first 10 years of life. Brain malformations, including focal cortical dysplasia and megalencephaly, constitute the most frequent causes of epilepsy in children. They have been recently linked to mutations in genes such as PIK3CA that are involved in brain development.

Dr. Franck Kalume

In collaboration with colleagues at the University of Washington, Dr. Franck Kalume developed mice with knockouts of SCN1A to define the neurons and networks of Dravet syndrome. His group determined that GABAergic interneuron dysfunction is primarily responsible for the presentation of the disease. They used the specialized mouse model, in which seizures can be reliably induced by increasing body temperature, to uncover the cellular and network mechanisms of specific symptoms such as sleep disorders and seizures. Dr. Kalume is using this deep understanding of the pathophysiology of Dravet syndrome to develop medical devices, drug treatments, and therapies for this pediatric orphan disease.

For epilepsy related to Leigh syndrome, Dr. Kalume collaborates with Dr. Simon Johnson, who uses Ndufs4 knockout mice as a model for the disease. Dr. Kalume’s group developed a mouse model in which Ndufs4 is knocked out in only GABAergic interneurons. This model isolates the epilepsy component of Leigh syndrome from other aspects of the disease. The Kalume lab is using the specialized Ndufs4 mice to work specifically on epilepsy in Leigh syndrome, including understanding its underpinning cellular mechanisms and identifying potential therapeutic targets.

Dr. Kalume also collaborates with Dr. Kathleen Millen, who uses CRISPR and other gene-editing methods to develop mouse models for brain overgrowth and other malformations. Drs. Kalume and Millen work with a specialized mouse model to study mammalian targets of rapamycin (mTOR)-related epilepsy. In addition, the Kalume group works with Drs. Filomena Pirozzi and Ghayda Mirzaa on brain organoid models of epilepsy. These studies are using electroencephalographic (EEG) technology to monitor the organoids while testing novel drug for these disorders.

Dr. Kalume is interested in partnerships to further develop medical device prototypes and discover and test candidate therapies for epilepsy including drugs and gene therapy. He is also interested in using advanced models of pediatric epilepsy to identify additional therapeutic targets.

Dr. Franck Kalume’s Faces of Research Video

Stage of Development

• Pre-clinical in vitro and in vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement

Publications

1. Bolea I, Gella A, Sanz E, Prada-Dacasa P, Menardy F...Kalume F, Quintana A. Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome. Elife. 2019;8. pii: e47163. doi: 10.7554/eLife.47163.
2. Williams AD, Kalume F, Westenbroek RE, Catterall WA., A more efficient conditional mouse model of Dravet syndrome: Implications for epigenetic selection and sex-dependent behaviors J Neurosci Methods. 2019 Sep 1;325:108315.
3. Kalume F, Oakley JC, Westenbroek RE, Gile J, de la Iglesia HO, Scheuer T, Catterall WA, Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome, Neurobiol Dis. 2015 May;77:141-54.
4. Cheah CS, Westenbroek RE, Roden WH, Kalume F, Oakley JC, Jansen LA, Catterall WA, Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome, Channels (Austin). 2013 Nov-Dec;7(6):468-72.
5. Kalume F, Westenbroek RE, Cheah CS, Yu FH, Oakley JC, Scheuer T, Catterall WA, Sudden unexpected death in a mouse model of Dravet syndrome, J Clin Invest. 2013 Apr;123(4):1798-808

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Kalume Laboratory