Developing a drug-inducible gene therapy for temporal lobe 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

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.