Figure 1｜KCC2 enhancer treatment restores excitation/inhibition (E/I) balance in the injured spinal cord to treat paralysis, pain and spasticity.
KCC2 upmodulation: a promising multi-modal therapy for SCI patients: Despite the urgent unmet need and many years of research progress, there are no FDA-approved drugs that treat paralysis after SCI. Along with debilitating sensory and motor paralysis, SCI patients suffer from spasticity that hinders their remaining motor abilities, and neuropathic pain that negatively impacts their quality of life. A monotherapy that could restore motor functions, and alleviate spasticity and chronic pain after SCI, would significantly improve the lives of people living with SCI, and those of their families. Based on the preclinical studies discussed herein, an oral, neuromodulatory KCC2 enhancer drug has the potential to treat paralysis, neuropathic pain and spasticity simultaneously after SCI, through restoring E/I balance and functionality within the spared neurons of the injured spinal cord (Figure 1). Such a non-invasive, first-in-class therapy would transform the therapeutic landscape for SCI patients. Moreover, some of the KCC2 treatment paradigms used in the efficacy studies above correlate with interventions for subacute or chronic SCI patients. Most novel therapeutic interventions (e.g., neuroprotection and/or neuroregeneration) are currently being developed for use in the acute period (from hours to days) after SCI, and thus would not be an option for the much larger chronic SCI patient population. Therefore, small molecule KCC2 treatments have a unique and promising potential to treat acute, subacute and chronic SCI patients.