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KCC2 Upmodulation

INCOMPLETE SPINAL CORD INJURY

Majority of spinal cord injuries are anatomically incomplete. Furthermore, according to post-mortem anatomy, it is common for clinically complete patients (without voluntary movement or sensation below the injury) to have residual spared tissue at the injury site. In 2018, Zhigang He’s lab demonstrated that the spared tissue can be reactivated through restoring expression of a protein, called KCC2 after spinal cord injury in mice (Chen et al., 2018, Cell).

REINSTATING THE BALANCE

KCC2 is a chloride transporter, which is downregulated after the injury, leading to overactivation of inhibitory interneurons. Brain and spinal cord are made up of two types of neurons – excitatory and inhibitor, which produce positive and negative signals, respectively. AAV-KCC2 reinstates excitation/inhibition balance (E/I) in the spared tissue leading to robust recovery of stepping ability in paralyzed mice (Chen et al. 2018).

“Restoring inhibition will allow the whole system to be excited more easily,” says He. “Too much excitation is not good, and too much inhibition is not good either. You really need to get a balance. This hasn’t been demonstrated in a rigorous way in spinal cord injury before.”

BREAKTHROUGH RECOVERY OF STEPPING ABILITY

This functional recovery is significant because stepping ability has been implicated as a limiting step for the functional recovery in SCI models. Figure 1A shows difference between the control AAV-GFP and AAV-KCC2 in locomotor function evaluated by the BMS score and stepping percent (note change in stepping percent from 0 to 80%). Figure 1B shows the pattern of hindlimb movement without injury (left), injury model with vehicle (middle) and injury model with treatment (right). Figure 2 shows videos of function recovery observed by scientists.

Figure 1A . source: cell.com
Figure 2A. source: cell.com

“For this fairly severe type of spinal cord injury, this is most significant functional recovery we know of,” says Dr. He. “We saw 80% of mice treated with this compound recover their stepping ability.”

TRIPLE-EDGED SWORD THERAPY FOR SPINAL CORD INJURY

Other groups have shown that KCC2-based therapies also improve spasticity and neuropathic pain, symptoms often associated with SCI (Sánchez-Brualla et al., 2018; Liabeuf et al., 2017). This makes AAV-KCC2, a multi-target treatment for SCI patients.

AXONIS Therapeutics is advancing this breakthrough discovery into a neuromodulating therapy for spinal cord injury and other neurological disorders.

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