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Developing a drug-inducible gene therapy for temporal lobe epilepsy

开发药物诱导的颞叶癫痫基因疗法

基本信息

批准号：
10800000
负责人：
EDWARD PEREZ-REYES
金额：
$ 53.15万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10800000
关键词：
Address Affect Agonist American Animal Model Anticonvulsants Basic Science Brain region Cells Characteristics Clinical Collaborations Convulsants Development Disease Dose Doxycycline Drug Screening Electric Stimulation Elements Enhancers Environment Epilepsy Equilibrium FDA approved Frequencies Gene Expression Goals Grant Hippocampus Hybrids Immune Kainic Acid Learning Maps Medical Medicine Memory Modeling Motor Seizures Mouse Strains Mus Neuromodulator Neurons Partial Epilepsies Patients Persons Pharmaceutical Preparations Pharmacotherapy Potassium Channel Randomized Recurrence Reproducibility Research Research Design Rodent Model Safety Seizures Side Site Sleep Structure System Technology Temporal Lobe Epilepsy Testing Universities Viral Vector antagonist clinical translation design drug development efficacy study excitatory neuron forest gamma-Aminobutyric Acid gene product gene therapy immunocytochemistry inhibitory neuron insight miniaturize neural circuit neuronal circuitry next generation novel overexpression preclinical study promoter side effect success targeted treatment

项目摘要

There are 3 million Americans with epilepsy. This research aims to develop a first-in-class drug- inducible gene therapy for the most common form of focal epilepsy, temporal lobe epilepsy (TLE). TLE affects half a million Americans, yet despite the size of this problem, medical treatment of TLE fails in a third of these patients. Clearly there is a large unmet clinical need for a treatment without side effects. The guiding hypothesis of these studies is that TLE is a circuit-based disease, requiring the development of next-generation gene therapies that target these circuits. Key technological advances made to address this hypothesis include: 1) development of novel animal models of TLE with spontaneous seizure characteristics that are amenable to drug screening; 2) mapping epileptic circuits using activity-dependent promoters; and 3) development of drug-inducible gene therapies that target specific circuits. It was discovered that electrical stimulation of a specific strain of mouse (VGAT-Cre) was sufficient to trigger limbic epilepsy. To extend the model to other strains of mice, electrical stimulation was combined with a chemoconvulsant, kainic acid. This hybrid approach effectively triggered spontaneous seizures in commonly used mouse strains, such as C57Bl/6. Importantly, the hybrid approach opened the door for studies using the TRAP2 strain, which has proven useful for circuit mapping studies. The drug-inducible gene therapy uses the well-established doxycycline (Dox) regulated system. The technological challenges were to miniaturize this system so it fits in viral vectors, reduce gene expression in the absence of the inducer (leak), and develop a toolkit of promoters to target neuronal subtypes. The goal is to develop a Dox-On system where Dox administration reduces seizures and that possible side effects can be reduced by lowering the Dox dose. Reducing leak to background levels is an important safety feature that has yet to be incorporated in any FDA-approved gene therapy. The mechanisms of action of many current antiseizure drugs are to either reduce the activity of excitatory neurons or enhance the activity of inhibitory neurons. By developing gene therapies that selectively target these types of neurons, the proposed studies will compare these two approaches. Key metrics for these therapies are to show they reduce spontaneous seizure frequency by 50% and target specific nodes in the epileptic circuit. Efficacy studies will use rigorous preclinical study designs with blinding, reproducibility, and target engagement. Contributing to the success of this study is a rich environment for clinical translation of basic research in animal models of epilepsy.

美国有300万癫痫患者。这项研究的目的是开发一种一流的药物