In mice, loss of hindlimb motion due to spinal cord injury was significantly reversed by DNA encoding hyper-interleukin-6 (hIL-6), a designer cytokine. The DNA was delivered by an adeno-associated virus (AAV), which was injected just once, 30 minutes after spinal cord injury, into the sensorimotor cortex. This intervention promoted the regeneration of corticospinal and raphespinal fibers, improvements that led to locomotion improvements, as determined by tests using the Basso Mouse Scale and an automated catwalk gait analysis system.
This work was accomplished by scientists at the Ruhr University of Bochum. Led by Dietmar Fischer, PhD, the scientists reported their findings in a paper (“Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice”) that appeared January 15 in Nature Communications.
“We demonstrate that cortical motoneurons project collaterals to serotonergic raphe neurons deep in the brain stem, allowing the release of hIL-6 to induce regenerative stimulation of serotonergic neurons,” the article’s authors wrote. “Thus, transneuronal stimulation of neurons located deep in the brain stem using highly potent molecules might be a promising strategy to achieve functional repair in the injured or diseased human central nervous system.”
Spinal cord injuries caused by sports or traffic accidents often result in permanent disabilities such as paraplegia. This is caused by damage to nerve fibers, so-called axons, which carry information from the brain to the muscles and back from the skin and muscles. If these fibers are damaged due to injury or illness, this communication is interrupted. Since severed axons in the spinal cord can’t grow back, the patients suffer from paralysis and numbness for life. To date, there are still no treatment options that could restore the lost functions in affected patients.
In their search for potential therapeutic approaches, Fischer and colleagues have been working with the protein hIL-6. “This is a so-called designer cytokine, which means it doesn’t occur like this in nature and has to be produced using genetic engineering,” explained Fischer, who is chair of cell physiology faculty of biology and biotechnology at Bochum.
In an earlier study, Fischer’s research group demonstrated that hIL-6 can efficiently stimulate the regeneration of nerve cells in the visual system. In the current study, the group induced nerve cells of the motor-sensory cortex to produce hIL-6 themselves.
To achieve this effect, the scientists used viruses suitable for gene therapy, which they injected into an easily accessible brain area. There, the viruses deliver the blueprint for the production of the protein to specific nerve cells, so-called motoneurons. Since these cells are also linked via axonal side branches to other nerve cells in other brain areas that are important for movement processes such as walking, the hIL-6 was also transported directly to these otherwise difficult-to-access nerve cells and released there in a controlled manner.
“Gene therapy treatment of only a few nerve cells stimulated the axonal regeneration of various nerve cells in the brain and several motor tracts in the spinal cord simultaneously,” Fischer pointed out. “Ultimately, this enabled the previously paralyzed animals that received this treatment to start walking after two to three weeks. This came as a great surprise to us at the beginning, as it had never been shown to be possible before after full paraplegia.”
The research team is now investigating to what extent this or similar approaches can be combined with other measures—such as neutralizing extracellular inhibitors at the lesion site or bridging the lesion site with permissive grafts—to optimize the administration of hIL-6 further and achieve additional functional improvements. They are also exploring whether hIL-6 still has positive effects in mice, even if the injury occurred several weeks previously.
“This aspect would be particularly relevant for application in humans,” Fischer stressed. “We are now breaking new scientific ground. These further experiments will show, among other things, whether it will be possible to transfer these new approaches to humans in the future.”
