Seizures with a focal onset, such as temporal lobe epilepsy (TLE), are a set of debilitating disorders that affect millions of people worldwide. Despite the size of this problem, medical treatment of TLE fails in most cases. For over 40 years, the only option left for these patients has been surgery to remove the temporal lobe. Therefore, the development of novel treatments that can prevent focal seizures will have a significant impact on the quality of life of many epilepsy patients. The hypothesis guiding this R21 grant is that silencing hyperactive neurons in the Entorhinal Cortex (EC) will prevent seizures. Substantial evidence in both animal models and human patients incriminate the role of EC neurons in TLE seizures. Preliminary data show that in rodent models of TLE, EC neurons have increased firing due to increased after-depolarizing currents and increased expression of Na channel subunits. The hypothesis is that knocking down the expression of the Na channel beta-4 subunit using short-hairpinned RNA (shRNA) will reduce seizures. Recombinant adeno-associated virus (rAAV) has emerged as the top choice for human gene therapy. An important safety feature is the ability to regulate gene therapy. This will be accomplished using a newly developed tetracycline regulator cassette that controls expression of the shRNA and requires drug for activation (doxycycline-ON). The overall goal is to develop a delivery system for the shRNA that can be used in the clinic and to test its efficacy in animal models of TLE.

Public Health Relevance

Temporal lobe epilepsy (TLE) is debilitating disorder that affects millions of people worldwide and is difficult to treat with medicines. This grant proposes an innovative approach to preventing these seizures -- silencing hyperactive neurons by knocking down the expression of Na channel subunits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS080061-01
Application #
8368393
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Whittemore, Vicky R
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$237,000
Indirect Cost
$87,000
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904