Medical Device Daily

Newly reported research in animals indicates hope for using embryonic stem cell-derived motor neurons transplanted into the spinal cord, to treat spinal cord trauma and other spinal disorders, as a way of restoring motor and muscle function.

The research, led by Douglas Kerr, MD, PhD, of theJohns Hopkins University School of Medicine (Baltimore) and funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Insitutes of Health – suggests that similar techniques may be useful for treating, in humans, such disorders as spinal cord injury, transverse myelitis, amyotrophic lateral sclerosis and spinal muscular atrophy.

David Owens, PhD, the NINDS program director for the grant that funded the work, told Medical Device Daily: “The key finding here, the big finding, in the spinal cord injury area,” is that for 30 years researchers “have been trying to find a way to get an axon, which is essentially the message-sending part of a neuron – out of the damaged spinal cord to the muscle. And this is the first time they've actually succeeded in doing that.

“It is a rather big breakthrough. It's proof of principle – it shows that it's not impossible to do that,” Owens said.

The researchers used a combination of transplanted, stem cell-derived motor neurons, containing chemicals capable of overcoming signals that inhibit axon growth.

The report, published in the July issue of Annals of Neurology, “provides a 'recipe' for using stem cells to reconnect the nervous system,” said Kerr. “It raises the notion that we can eventually achieve this in humans,” while adding the caveat of much initial research that such an application has “a long way to go.”

Kerr and colleagues cultured embryonic stem cells from mice with chemicals that caused them to differentiate into motor neurons. Just before transplantation, they added three nerve growth factors to the culture medium. The NIH said most of the cells were also cultured with a substance called dibutyrl cAMP that helps to overcome axon-inhibiting signals from myelin, which insulates nerve fibers in the spinal cord.

The cells were transplanted into eight groups of paralyzed rats. Each group received a different combination of treatments, with some groups receiving a drug called rolipram before and after the transplants. Rolipram, also approved to treat depression, helps to counteract axon-inhibiting signals from myelin, the NIH said.

Some animals also received transplants of neural stem cells that secreted the nerve growth factor GDNF into the sciatic nerve.

Upon examination three months after the implant, researchers found that the rats that had received the “full cocktail” of treatments had “several hundred transplant-derived axons extending into the peripheral nervous system, more than in any other group.

The axons in those animals reached all the way to the gastrocnemius, a muscle in the lower leg, and formed synapses with the muscle. Within four months after transplantation, the rats showed an increase in the number of functioning motor neurons and about a 50% improvement in hind limb grip strength.

“We found that we needed a combination of all of the treatments in order to restore function,” Kerr said.

After six months, those rats treated on only one side of the body with the cocktail showed that 75% regained the ability to bear weight on the GDNF-treated limbs and to take steps and push away with the foot on that side of their body.

Owens told MDD that “many previous studies have shown that damage within the cord itself can be repaired” or that neuro-protection can help.

“You can remyelinate” – meaning restore the myelin sheath – “and overcome certain inhibitor influences within the cord, but to actually get the axon – the message sender – out of the cord and into the muscle has not been accomplished until now,” Owens said.

The next steps would involve “extending these findings to other types of injury models.”

“It would be nice to generalize it to other models in terms of moving toward more therapeutic applications,” he said. As a potential difficulty for this, he said that in rats the distance that the axon has to travel to the muscle is much shorter than in humans.

Owens also said that to expand the findings into humans would require using other cells that are “more amenable, because these are mouse cells into a rodent” in the current findings.

And there is currently no large-animal model for motor neuron degeneration, Kerr acknowledged. Hence he and his colleagues are working to develop a pig model.

Kerr told the NIH that it has only recently become possible to grow motor neurons from human embryonic stem cells. And the NIH said that the researchers would need to test human embryonic stem cells to learn if they will work in the same way as the mouse cells in Kerr's research.