Reliable, high throughput KV7 assays are important because KV7 ion channels play a key role in regulating neuronal excitability, which is closely linked to both pain signalling and seizure activity.
The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines were introduced in 2005 to evaluate the proarrhythmic liability of new drugs. They were implemented in response to the discovery that inhibition of the rapid delayed rectifier potassium current (IKr), which is encoded by the human ether-à-go-go related gene (KV11.1), is associated with prolongation of the QT interval and the potentially deadly arrhythmia, Torsades de Pointes.
The guidelines utilise hERG inhibition and QT interval prolongation as surrogate markers of proarrhythmic liability, which are highly sensitive and have proven effective at preventing proarrhythmic drugs from reaching the market. However, these markers have low specificity, with only a modest correlation between hERG inhibition, QT prolongation and proarrhythmic liability. Therefore, to address these limitations, the Comprehensive in Vitro Proarrhythmia Assay initiative was launched by the Food and Drug Administration (FDA) in July 2013. The CiPA initiative aims to improve the accuracy and reduce the cost of predicting cardiac liability using three ‘pillars’:
1. Compounds will be profiled against a panel of human ventricular ion channels.
2. This in vitro data will be incorporated into an in silico model of a human action potential to provide a proarrhythmic risk classification.
3. Compounds will be tested using human induced pluripotent stem cell- derived cardiomyocytes to confirm the risk classification derived from the in silico model.
These efforts more recently have resulted in the updates to the original ICH S7B/E14 guidance in the form of a Q&A document. The recommendations form this document now form the basis of regulatory requirements for IND enabling GLP studies as related to preclinical and clinical assessment of arrhythmia liability.
Reliable, high throughput KV7 assays are important because KV7 ion channels play a key role in regulating neuronal excitability, which is closely linked to both pain signalling and seizure activity.
Kv7 ion channels are highly relevant to epilepsy because they are voltage gated potassium ion channels that help regulate neuronal excitability and suppress excessive electrical firing in the brain.