Modern drug-discovery research over the last two decades aimed at improving the pharmacological treatment of epileptic seizures has resulted in more than a dozen new anti- epileptic drugs (AEDs). Although these new AEDs may have reduced side effects and drug- drug interactions, the percentage of epileptic patients who continue to have seizures while treated with the new AEDs has remained at 30-40% for >20 years. In this proposal, we aim to develop a gene-therapy approach to treat pharmacoresistant epilepsy through the implementation of a novel "designer" receptor system that should not affect normal brain function, and therefore is less likely to have significant side-effects. This system will utilize adeno-associated viral (AAV) delivery of a modified human ?1glycine receptor with reduced glycine sensitivity and enhanced sensitivity to the FDA-approved drug, ivermectin. Recombinant AAVs will be genetically optimized for expression in epileptic neurons and tested for efficacy in animal models of epilepsy. Ivermectin, which has minimal effects on the normal brain at the very low concentrations necessary to activate the modified receptor, will then act as an AED specifically at the site of generation of the epileptic seizures, thus suppressing epileptic seizures without affecting normal brain function. These studies are intended to lead directly to clinical trials. The use of a human receptor and an FDA approved drug should facilitate this advancement from bench side to clinical treatment so that by the end of the 4 year grant, we will have a gene transfer vector in hand that could be considered for clinical trials in pharmacoresistant epilepsy patients.

Public Health Relevance

An enormous challenge in the clinical treatment of epilepsy is that 30-40% of the people with epilepsy continue to have seizures in spite of many newly-discovered antiepileptic drugs. We propose to develop a novel system for treating this pharmacoresistant epilepsy that will involve a gene-therapy approach based on novel designer receptors and a novel FDA- approved drug that should produce minimal effects on the normal brain. Successful completion of these studies is intended to lead directly to clinical trials for te treatment of pharmacoresistant epilepsy patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079274-01
Application #
8333833
Study Section
Special Emphasis Panel (ZNS1-SRB-B (32))
Program Officer
Fureman, Brandy E
Project Start
2012-06-01
Project End
2016-02-29
Budget Start
2012-06-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$324,522
Indirect Cost
$70,699
Name
University of Utah
Department
Physiology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Dingledine, Ray; Varvel, Nicholas H; Dudek, F Edward (2014) When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv Exp Med Biol 813:109-22
Spampanato, Jay; Dudek, F Edward (2014) Valnoctamide enhances phasic inhibition: a potential target mechanism for the treatment of benzodiazepine-refractory status epilepticus. Epilepsia 55:e94-8
Galanopoulou, Aristea S; Kokaia, Merab; Loeb, Jeffrey A et al. (2013) Epilepsy therapy development: technical and methodologic issues in studies with animal models. Epilepsia 54 Suppl 4:13-23