The spinal cord is like a superhighway for the body’s nervous system. Partial injuries, like lane closures, let fewer brain signals through, but complete spinal cord injuries are akin to highway closures. No signals cross the injury site to the other side, paralyzing the body below the site of the injury.
Today, there’s no way to restore motor function – such as the ability to walk – below the injury site. A recent study published in Science, however, shows that walking can be restored even after complete spinal cord injuries in mice. It will be years, however, before the therapy can be used to treat humans.
How Can We Restore Motor Function?
A team of scientists from multiple institutions – specifically, the Swiss Federal Institute of Technology (EPFL), the research and treatment center NeuroRestore, the Wyss Center for Bio and Neuroengineering, and the University of California, Los Angeles – have restored the ability to walk in mice by using gene therapy.
The key, they learned, isn’t just causing nerves to grow across the injury. They achieved that five years ago. Instead, the crucial element in restoring motor function is for the nerves to reconnect to their natural places on the other side of the injury. When they achieved that recently – to use the highway analogy – they not only had built a bridge across a chasm but had aligned the lanes properly.
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RNA Sequencing and Motor Function
To do this, Mark Anderson, director of central nervous system regeneration at NeuroRestore and colleagues at EPFL, devised a multipronged approach.
First, they used single-cell RNA sequencing to identify the neuronal cells that were most likely to regenerate and restore motor function. Then they traced the connections (called axons) of those neurons to identify their natural connection sites.
Once they did that, regeneration work could begin. Anderson and his team reactivated the neurons’ ability to regenerate, caused certain proteins in the body to form a matrix to support the new cells as they grew through the body’s tissue, and administered other molecules to guide the regenerative nerve fibers to their natural positions below the injury site lesion.
This approach is similar to the body’s natural repair mechanisms and resulted in “substantial recovery of walking after complete spinal cord injury,” they explained in their paper.
What Are the Potential Challenges of Regenerating Nerve Cells?
“We know this therapy is effective in mice, but we don’t yet know if it will be equally robust in larger animals,” says Anderson.
The biggest potential hurdle, he says, is that the larger the animal, the greater the distance the regenerating nerve cells must travel “to reach relevant target regions in a large animal’s – or human’s – spinal cord.”
“We’re working on technology and methods to achieve this […] and are scaling this intervention up into non-human primate models of spinal cord injury,” Anderson continues. For example, “A potential way to span greater distances is to use gradients of growth factors that can be used to guide the axons.” That phase of development will likely take three to five years, after which human studies may begin.
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How Long Before Humans Could Restore Motor Functions?
Research involving mice is standard practice in medicine, but success in mice doesn’t necessarily correlate to success in humans, or even in large animals.
“Large animals showed only minimal functional restoration with regenerative therapies compared to rodents demonstrating significant recovery (after therapy),” says Igor Lavrov, neurologist and neuroscientist at the Mayo Clinic. Consequently, multiple attempts to translate successful regenerative therapy in mice to humans have failed.
As the research scales to larger and larger animals, the scientists will need to fine-tune their work to identify the specific connections and their targets, based on the potential for functional recovery, Lavrov points out.
Can Gene Therapy Cure Paralysis?
They also must determine whether gene therapy alone is enough to restore normal motor function. Currently, mice that regain motor function after being treated by the EPFL team walk about as well as those that were partially injured.
To address that challenge, NeuroRestore is developing a brain-spinal cord interface and targeted epidural spinal stimulation (called TESS).
As Gregoire Courtine, an author of the study, says in a news release, “We believe a complete solution for treating spinal cord injury will require both approaches – gene therapy to regrow relevant nerve fibers, and spinal stimulation to maximize the ability of both these fibers and the spinal cord below the injury to product movement.”
Testing those therapies with gene therapy is still likely years away, but they are expected to act synergistically, Jordan Squair, a lead author of the study, adds. “These complementary technologies will integrate the regenerating axons into existing spinal cord circuitry below the lesion, and will likely enhance neurological function.”
This work focused solely upon restoring motor function. Restoring sensation involves a different set of axons, Anderson says. “We haven’t yet targeted these for regeneration.”
“This study adds a significant component to the field of spinal cord regeneration,” Lavrov says. In fact, he speculates, “Ensuring the nerve cells grow across the injury and re-establish connections at the originally determined places may become a requirement for future regeneration studies aimed at restoring motor function.”
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