Excitation/Inhibition (E/I) imbalance within neuron circuits is a pathological hallmark of various neurological disorders, including epilepsies, neurodevelopmental disorders and CNS injuries. Modulating neurons to restore E/I balance can rescue brain functions.
KCC2 is a CNS-specific, electroneutral chloride transporter that is essential for enabling neuron responses to inhibition. KCC2 extrudes chloride to ensure low chloride concentrations in neurons, which allows inhibition upon GABA receptor activation.
RESTORING E/I BALANCE
In neurodevelopmental disorders and after injury to the CNS, KCC2 is downregulated leading to E/I imbalance within the neurons. Without KCC2, affected neurons no longer respond appropriately to inhibitory inputs, causing dysfunction in neuron circuits and impaired neurological functions, such as pain, paralysis, spasticity, seizures and intellectual disabilities.
Pipeline-in-a-Pill: KCC2-Hypofunction in E/I Disorders
Treatments that enhance KCC2 restore E/I balance and rescue functions in several neurological disorder models (e.g., CNS injuries, pain, neurodevelopmental disorders, epilepsies). However, no KCC2 drugs exist on the market. At Axonis, we are advancing a first-in-class oral KCC2-potentiating small molecule into the clinic. Fine-tuning chloride homeostasis in CNS neurons enables them to respond to GABA-mediated inhibition, without a need for global depressive effects on the brain.