Combined use of a vector encoding a modified receptor and its exogenous agonist in the treatment of seizures
The invention provides methods and materials for treating a seizure disorder such as epilepsy in a patient which employ a vector encoding a modified receptor, the so-called “DREADD” receptor being characterised by (i) a decreased responsiveness to its endogenous activating ligand (ii) a retained or enhanced responsiveness to an exogenous agonist. The modified receptor is expressed in neurons of a seizure focus in brain of the patient, and an exogenous agonist is administered which activates the modified receptor to reversibly alters the excitability of the neurons in the seizure focus leading to synaptic silencing or other inhibition.
1. A method of treating a seizure disorder, which is focal epilepsy, in a patient suffering from said disorder,
wherein either
(a) said patient has previously been administered a vector encoding a modified receptor,
wherein the modified receptor is a human muscarinic acetylcholine receptor M4, which is a Gi protein-coupled receptor (GPCR), coupled via a Gi-protein to a G protein-coupled inwardly rectifying potassium channel (GIRK), and
wherein the modified receptor is characterised by (i) a decreased responsiveness to its endogenous activating ligand and/or (ii) a retained or enhanced responsiveness to an exogenous agonist, or
(b) administering to the patient said vector,
wherein the modified receptor is encoded by a nucleic acid operably linked to a neuronal cell type-specific promoter such that said modified receptor is expressed in excitatory neurons of a seizure focus in brain of the patient;
which method comprises subsequently administering to said patient an exogenous agonist selected from clozapine, clozapine-N-oxide and perlapine,
whereby the presence of said agonist in the brain of the patient activates said modified receptor,
whereby activation of said modified receptor reversibly inhibits the excitability of, and neurotransmission by, the excitatory neurons in the seizure focus.
2. The method of claim 1 , wherein the exogenous agonist is administered automatically either (i) by a device that is either coupled to an automated seizure detection mechanism, or (ii) in response to a predicted seizure by EEG analysis.
3. The method of claim 1 , wherein the promoter is the CaMk2A promoter.
4. The method of claim 1 , wherein the exogenous agonist is clozapine-N-oxide, which is optionally administered as clozapine.
5. The method of claim 1 , wherein the exogenous agonist is perlapine.
6. The method of claim 1 , wherein the exogenous agonist is administered prior to the patient having an epileptic seizure or during an epileptic seizure.
7. The method of claim 6 , wherein the exogenous agonist is administered within 30 minutes before or 24 hours after the human has an epileptic seizure.
8. The method of claim 1 , wherein the modified GPCR includes at least modifications at positions 113 and\or 204.
9. The method of claim 8 , wherein the modifications are Y113C and/or A230G.
10. The method of claim 1 , wherein the vector is a viral vector.
11. The method of claim 10 , wherein the viral vector is selected from the group consisting of: an adenovirus vector, an adeno-associated vector, a herpes virus vector, a retrovirus vector and a lentivirus vector.