During seizures or pain-induced inflammation, excess chemical mediators suppress potassium channels mediating neuronal activity and thereby inactivate new generation anti-epileptic drugs and painkillers acting on those channels. The invention describes a gene therapy using a genetically-engineered potassium channel that reduces adverse effects by silencing neuronal hyperactivity while maintaining normal neuronal activity in the presence of chemical mediators to treat epilepsy and pain.
Mutations in the KCNQ2 gene encoding a voltage-sensitive potassium channel can cause familial epilepsy. These potassium channels generate a persistent potassium current that sets the tone of neuronal activity. During seizures or inflammation, excess spillover of chemical mediators (neurotransmitters) suppressed channel activity and current leading to increased neuronal firing or hyperactivity. Current small molecule anti-epileptic drugs and painkillers cannot fully activate or preserve potassium channel activity in the presence of neurotransmitters. Furthermore, surgical removal of the brain area triggering seizures, the only available treatment for epilepsies resistant to drugs, can cause functional complications and adverse side effects.
Gene therapy would replace expensive epilepsy surgery, reduce adverse side-effects of drugs or surgery, and permanently block neuronal hyperactivity underlying pain. The invention provides a promising approach of using genetically-engineered human Kv7.2 channels to treat epilepsy and neuropathic pain. The invention proposes gene therapy using genetically-engineered neuronal potassium channels introduced into the brain via injection of an adeno-associated virus (AAV) carrying mouse or human Kv7.2 protein sequence.
§ Gene therapy for treating epilepsy and pain
§ Replaces expensive epilepsy surgery and improve patients’ quality of life
§ Reduces adverse side-effects associated with drugs or surgery
§ Saves healthcare cost for pain management considering the procedure permanently suppresses neuronal hyperactivity for longer lasting effect compared to temporal effects of local anesthetics
§ Determined the comprehensive molecular pathway governing M-current suppression§ Identified and validated importance of phosphorylating key amino acid residues on Kv7.2 protein that mediate M-current suppression
§ In vitro demonstrated Kv7.2 channel is suppressed during seizures therefore preserving channel activity during seizures might prevent seizures
§ Discovered in control mice valproic acid (anti-epileptic drug) controls seizures by preserving the M-current, but it cannot fully prevent seizures due to its indirect mechanism and low potency
§ In vivo demonstrated mutant Kv7.2 channel lacking the phosphorylation site can protect neuronal activity against drug-induced seizures
§ Prospective plans include developing AAV of mutant human Kv7.2 protein and verifying therapeutic value of this procedure