Therapeutic window for pharmacological KCC2 neuromodulation
Funded in: 2021, 2022, 2023
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Problem: Novel neuromodulating drug could reactivate dormant tissue
Target: Usage of potassium/chloride transporter (KCC2)
Goal: Oral drug to greatly improve the quality of life
Most spinal cord injuries (SCI) are incomplete. Many patients even with complete motor impairment possess spared neural connection spanning across the injury site. Neuromodulation via exercise or electrical stimulation improves function by reactivating spared connections. However, a novel pharmacological, neuromodulating drug could reactivate those spared, but dormant tissue leading to recovery of sensorimotor and autonomic functions. Additionally, such treatment could neutralize other post-traumatic complications such as neuropathic pain and spasticity. This oral drug would greatly improve the quality of life.
After SCI, a potassium/chloride transporter (KCC2) is decreased leading to dysfunction of spinal neurons. Scientists found that this transporter is an attractive target for treating SCI and its co-morbidities, yet there are no approved drugs that specifically enhance function or directly activate KCC2.
An initial screen for KCC2 enhancers identified several promising lead compounds. Extensive biochemical studies led to the development of AXN compounds, novel analogs with increased potency. The goal is to determine optimal therapeutic time window of lead AXN compound in acute and chronic SCI. The researchers will evaluate effects of early or delayed treatment with AXN compound on locomotor/bladder function, chronic/neuropathic pain, and spasticity in a clinically relevant rat SCI model.
KCC2-enhancing therapy with an orally delivered drug has a unique opportunity for neuromodulation in acute and chronic SCI. The work proposed herein, to determine optimal therapeutic time window, will be the key for further translational development and clinical trials with this promising intervention.