Engineering potassium channel gene therapies in mouse and human models of temporal lobe epilepsy

Active Project Grant Awarded Last action

Award ID
F31NS145652
Recipient
Awarding agency
Obligated
$43,097

Award facts

Assistance listing
93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
Completion date 0% complete
Place of performance
California, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures that stem from uncontrolled abnormal neural electrical activity. Recurrent seizures may lead to a constellation of symptoms including, but are not limited to, altered levels of consciousness, convulsions, impaired memory, and changes in behavior and sensation. This debilitating disease affects an estimated 50 million individuals worldwide contributing to significant morbidity and mortality. Currently, there are approximately 30 distinct antiepileptic medications in use owing to the expansive possible drug regimens and treatment options. Despite the existence of many antiepileptic medications, approximately 30-40% of patients exhibit resistance to treatment. Following the failure to respond, the chances of responding become less likely with each successive new treatment prescribed, highlighting the need for alternative therapeutic approaches. To date, the majority of therapeutic approaches consist of small molecule drug regimens which are often non-specific, can lead to significant side effects, and overall have limited efficacy. Therefore, rather than focus on small molecule drug discovery, I believe that gene therapy may be a promising alternative as IT can be fine- tuned to target specific cell types, brain regions, and modulate various molecular pathways that may contribute to seizure propagation and epileptiform activity. While there is existing evidence that gene therapies may have the potential to limit seizure like activity, such as engineered ION channels, very few have been designed for use in patient populations. To address this unmet need, I seek to systematically evaluate established, and engineer novel ION-channel based gene therapies. I hypothesize that a potassium channel- based genetic therapy regulated by conserved promoter sequences in excitatory neurons will mitigate seizure-like activity while maintaining basal level neuronal activity. To test this hypothesis, I will pursue three orthogonal goals. First, I will test the ability of existing and novel engineered potassium channel-based gene therapies to limit seizure like activity in ipsc-neurons and cultured organotypic human brain tissue (aim 1). In parallel, I will test long term safety and stability of the existing and novel engineered potassium channel-based gene therapies in a recurrent seizure mouse model via continuous EEG monitoring and behavioral assays (aim 2). Lastly, using established methods, I will identify cell type specific promoters to successfully drive excitatory neuron expression in cultured organotypic resected human brain tissue utilizing adeno-associated virus, immunofluorescent labeling, and single nuclear sequencing (aim 3). In doing so, I will help to establish foundational knowledge required for the successful implementation of genetic based therapies in the context of neurological disease.

Quick answers

Who received award F31NS145652?

F31NS145652 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on December 1, 2026.

How much is award F31NS145652 worth?

$43,097 has been obligated on F31NS145652.

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