Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurological disorder that affects 5 out of every 100,000 people worldwide and proves fatal in most patients within 3 to 5 years of diagnosis. The most frequent cause of death in ALS patients is breathing failure because, as the disease progresses, it kills the nerve cells that cause the respiratory muscle to contract.
Although scientists have studied this devastating disease for almost two centuries, they have developed few effective treatments and no cure. Still, advancements are being made. A new study conducted by researchers from the UW School of Veterinary Medicine shows the potential for two complementary treatments—stem cell therapy and intermittent exposure to low oxygen—to preserve and even restore breathing capacity in rats with a condition similar to ALS in humans.
“This study represents a convergence of two different approaches that we think will be mutually reinforcing,” says Gordon Mitchell, professor of comparative biosciences at the SVM and co-principal investigator for the study.
ALS causes paralysis by killing motor neurons, the nerve cells that send electrical impulses from the spinal cord to the muscles to produce movement. When the disease attacks the cervical spinal cord, phrenic motor neurons begin to die and stop sending signals via the phrenic nerves to the diaphragm—the respiratory muscle essential to breathing. This degeneration leads to death from respiratory failure.
Stem Cell Therapy
The researchers tested the potential of two treatments for addressing this problem in laboratory rats in the end-stage of ALS and found very promising results. One part of the study, led by Clive Svendsen, now director of the Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles, used human neural progenitor stem cell transplants to repair the environment around the phrenic motor neurons. Although the treatments did not replace dying neurons, they slowed the rate at which the cells died and helped preserve breathing function.
“The human stem cells migrated toward areas of damage and restored respiratory output,” says Svendsen, whose team performed the stem cell injections on the UW-Madison campus while he was co-director of the UW Stem Cell and Regenerative Medicine Center. “They seem to act as support or nursing cells that prevent the neurons from dying.”
“We found that the stem cells didn’t need to be right next to the phrenic nerve cells to have an impact,” says Nicole Nichols, a Parker B. Francis post-doctoral fellow who conducted all of the neurophysiological analysis for the study at the SVM. “As long as they’re in relatively close proximity, they can still have a therapeutic effect.”
This is an important finding for potential clinical translation to humans, Nichols says, because it suggests that as long as the stem cells are injected close to the phrenic nerve cells, they will make their way to where they are needed and have a positive effect.
For the second part of the study, Nichols, Mitchell, and their team tested the effects of a novel low-oxygen treatment on the ability of surviving motor neurons to generate breathing. Acute intermittent hypoxia (AIH) delivers intervals of air containing non-damaging, low oxygen levels to trigger a response that strengthens the motor neuron signals. AIH can help stimulate function in muscles associated with breathing and limbs and has been applied successfully to spinal injury cases in humans. In this study, the method restored the function of phrenic nerves in the rats to normal levels, helping to restore the ability to breathe despite the loss of a significant amount of motor nerve cells.
“It’s fascinating that just one half hour of exposure to AIH can have such a robust effect,” says Nichols. “It actually enhances the output of the surviving neurons.”
“Together, the findings tell us that these two treatments have complementary translational potential to treat breathing deficits in ALS patients,” says Mitchell.
Mitchell says the study, which was funded by National Institutes of Health and the ALS Association, is unusual because most ALS research and experimental treatments target the loss of function in patients’ limbs, which does not address the most common cause of mortality in ALS patients. “There is no therapy that is going to prolong their lives unless it also improves breathing,” he says.
Still Work to Be Done
According to Svendsen, the findings have informed other work that has wider implications for humans. The California Institute of Regenerative Medicine has provided him with funding to design and carry out a trial in humans that uses similar stem cells in ALS patients, although this particular study will also focus on lower spinal cord and leg function. In addition, Mitchell and his team are undertaking studies using a similar AIH method to help improve leg strength and walking in patients with mild spinal cord injuries.
“Ultimately, we would like to use AIH in ALS patients,” says Nichols. “If we can improve their breathing even by a small amount, it would be a huge step in increasing their quality of life.”
The study is published in the American Journal of Respiratory and Critical Care Medicine.