According to the National Spinal Cord Injury Association, as many as 450,000 people in the U.S. are living with a spinal cord injury (SCI). Other organizations conservatively estimate this figure to be about 250,000. Annually an estimated 11,000 SCIs occur in the U.S. Most of these are caused by trauma to the vertebral column, affecting the spinal cord’s ability to send and receive messages from the brain to the systems that control sensory, motor and autonomic function. Normally, this affects function below the level of injury.
According to the Centers for Diseases Control and Prevention (CDC), SCI costs the nation an estimated $9.7 billion each year. Pressure sores alone, a common secondary condition among people with SCI, cost an estimated $1.2 billion.
The majority of people with spinal cord injury are paralyzed from the injury site down, even when the cord is not completely severed. The question is, why don’t the intact portions of the spinal cord keep working? Researchers at Boston Children’s Hospital have discovered new insights into why these nerve pathways remain quiet. In a recent study, led by Zhigang He, PhD, in Boston Children’s F.M. Kirby Neurobiology Center, demonstrated that a small-molecule compound, given systemically, can revive dormant neural circuits in paralyzed mice, restoring the mice’s ability to walk.
“For this fairly severe type of spinal cord injury, this is most significant functional recovery we know of. We saw 80 percent of mice treated with this compound recover their stepping ability.” -Dr. Zhigang He
Previous animal studies examining spinal cord repair have focused on sprouting new axons from healthy ones. Although axon regeneration and sprouting have been achieved, the impact on motor function post injury remains unclear. Some studies have used neuromodulators to simulate the spinal circuits, but have achieved sporadic success and uncontrolled limb movement.
He and colleagues took a pharmacological approach based on successful epidural electrical stimulation strategies. Electrical stimulation, in which a current is applied to the lower portion of the spinal cord, is the only treatment known to be effective in patients with spinal cord injury. Unfortunately, epidural stimulation is only effective during application, so when the stimulation is removed, the effect is gone as well.
The study examined a selection of compounds known to alter the excitability of neurons, with the ability to cross the blood-brain barrier. Each compound was administered to paralyzed mice afflicted with severe spinal cord injuries with some nerves intact, for a period of eight to ten weeks. One compound in particular, called CLP290, showed the most promise in the study. After treatment with CLP290 for four to five weeks, paralyzed mice regained stepping ability.
CLP290 is known to activate the cell membrane protein KCC2, that transports chloride out of neurons. After spinal cord injury, neurons produce dramatically less KCC2 and cannot respond normally to signals from the brain. Effectively, the brain’s commands telling the limbs to move are not relayed.
Restoring KCC2 through the use of CLP290 or genetic techniques allows neurons to receive signals properly, balancing the overall neural circuit and making it more responsive to input. This had the effect of reawakening spinal circuits previously disabled by injury.
This discovery opens up the possibility for combination treatment, or other compounds that act as KCC2 agonists. Such drugs, or gene therapy to restore KCC2, could be combined with epidural stimulation to maximize patient function after spinal cord injury.
“We are very excited by this direction,” says He. “We want to test this kind of treatment in a more clinically relevant model of spinal cord injury and better understand how KCC2 agonists work.