DREADD Receptor Seizure Suppression via Exogenous Ligand
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for treating epilepsy, particularly focal epilepsy, face challenges in effectively suppressing seizures without impairing normal brain function, as they often require permanent alteration of neuronal excitability or rely on invasive light delivery methods that are inefficient due to light attenuation in brain tissue.
Innovation Solution
A novel therapeutic system using vectors to express a modified receptor that alters neuronal excitability only when activated by a specific exogenous ligand, ensuring targeted and temporally limited seizure suppression by administering a modified G protein-coupled receptor, such as hM4Di, coupled with a Gi-protein to a G protein-coupled inwardly rectifying potassium channel, which is insensitive to endogenous neurotransmitters but responsive to clozapine-N-oxide (CNO).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If viral delivery of transgenes that alter excitability permanently is used, then seizure suppression is achieved, but essential function of circuits near the seizure focus is impaired
Solution Approach 1:
The patent applies dynamics by making the receptor expression reversible and controllable in time. The modified receptor (DREADD) is expressed permanently in neurons, but its functional effect is dynamically controlled through temporary administration of the exogenous ligand CNO, allowing seizure suppression only when needed while preserving normal function at other times.
Solution Approach 2:
The patent changes the activation parameter of the receptor from responsiveness to endogenous neurotransmitters to responsiveness to an exogenous ligand (CNO). This parameter change allows selective activation only when the exogenous ligand is administered, preventing unwanted activation by normal brain chemistry while maintaining the ability to suppress seizures on demand.
2Reliability
If optogenetic methods are used to suppress seizures on demand, then seizure suppression is achieved, but implantation of optical devices is required and light delivery is inefficient
Solution Approach 1:
The patent replaces the mechanical/optical system (light delivery devices) with a chemical system (pharmacological administration of CNO). The modified receptor responds to the chemical ligand CNO, which can be administered systemically without invasive devices, eliminating the need for complex optical implantation while achieving the same functional outcome of on-demand seizure suppression.
3Reliability
If light of appropriate wavelength, intensity and duration is delivered to transduced neurons, then seizure suppression is achieved, but strong attenuation of light in brain tissue occurs
Solution Approach 1:
The patent substitutes the optical energy delivery system with a chemical delivery system. Instead of delivering light energy that is strongly attenuated by brain tissue, the system uses pharmacological administration of CNO, which can cross the blood-brain barrier and reach target neurons efficiently without the energy loss problems inherent in optical delivery through tissue.
4Object-affected harmful factors
If modified receptors insensitive to endogenous neurotransmitters are used, then selective activation is achieved, but responsiveness to exogenous agonist must be maintained
Solution Approach 1:
The patent applies local quality by creating a receptor with highly specific ligand binding properties. The modified DREADD receptor has been engineered to have high selectivity for the exogenous ligand CNO while being insensitive to endogenous neurotransmitters. This localized specificity at the molecular binding site allows selective activation only by the intended ligand without cross-reactivity with normal brain chemistry.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach effectively reduces seizures in both acute and chronic models of epilepsy with minimal impact on normal brain function, as the receptor's effect is localized and reversible, offering a promising solution for drug-resistant epilepsy cases without the risks of permanent neuronal changes or invasive light delivery.
Implementation Method 1
the modified receptor is the G protein-coupled receptor (GPCR) human muscarinic acetylcholine receptor M 4 which is coupled via a Gi-protein to a G protein-coupled inwardly rectifying potassium channel (GIRK)
Implementation Method 2
activation of said modified receptor reversibly inhibits the excitability of, and neurotransmission by, the neurons in the seizure focus
Data Source
Figure 1a~1f
Figure 2a~2f
Figure 3a~3d
AI summary
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.