Stanley Appel, M.D., left, with Chris Rice

Stanley Appel, M.D., left, with Chris Rice

The same immune process responsible for arthritis and juvenile diabetes could be the one of the "hits" that contributes to the degenerative nerve disorder amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. That process is called inflammation.

Neurologists theorize that inflammation may contribute to the disease along with the person's genes and surrounding environment.

"In non-familial ALS, which is 90 percent of the cases with ALS, it is likely that there is an environmental trigger for the disease," said Stanley Appel, M.D., chair for the department of neurology and director of the MDA/ALS clinic at Baylor College of Medicine. "But ALS is not that common, so that particular person also has to be sensitive to the environmental trigger. That is what I call a minimum of a two-hit phenomenon. You have to have both for the disease to occur." That sensitivity could be a gene or something not yet identified.

ALS researchers are investigating the possibility that inflammation is a "third hit" that may contribute to ALS. Damage to motor neurons may cause the body to launch an overzealous inflammatory counter attack, killing the motor neurons, and launching the chain reaction that causes the degenerative disease.

Inflammation may provide answers to some puzzling questions about the disease. Researchers have found that when they inject a mutated SOD1 gene, associated with the killing of motor neurons, into an animal model, the animal develops the disease. However, when the gene is injected directly into the motor neurons, the animal does not develop the disease.

One theory about this phenomenon is that the nervous system's immune cells called microglia are responsible for the motor neuron injury. Located in the brain and spinal cord, microglia normally clear away dead cells after injury and in turn attack invaders to the body like bacteria.

"So what we are saying here is if the motor neuron doesn't die by itself, there must be accomplices responsible for killing it, and these accomplices are part of an inflammatory reaction," Appel said. "The inflammation is what is doing the cells in, not the original causes."

Slight damage to the motor neuron or abnormal microglia sends signals that start the inflammation process. "Inflammation is a community response, and is triggered by multiple factors," Appel said. "There are multiple blocks and checks in this system and when these blocks and checks don't work, that's when you get the disease."

Based on the theory that a faulty immune system may contribute to ALS, Appel together with Uday Popat, M.D., and Malcolm Brenner, MBBCH, Ph.D., at Baylor's Center for Cell and Gene Therapy, are conducting a trial in humans using bone marrow transplantation as a treatment for the disease. The bone marrow in ALS patients is wiped out and replaced with bone marrow stem cells from one of their siblings. Baylor is the only center in the country participating in the trial. So far, six patients have had bone marrow transplants.

"It is too early to tell how the trial is going, but we are hopeful," Appel said. "Two patients are doing spectacularly well. Their disease has not progressed in seven months. You might say that two of six are not very good odds, but, it is possible that these two might not be doing so well without aggressive intervention. However, to be honest, these two might also have done well without the transplant. Time will tell."

How the disease works

The degeneration occurs in the motor neurons that control communication from the spinal cord to the muscle, called lower motor neurons, and also from the brain to the spinal cord, called upper motor neurons. Both upper and lower motors are necessary for muscle contraction and movement.

Degeneration of the motor neurons leads to:

  • weakness,
  • twitching of the muscles,
  • muscle atrophy, stiffness,
  • and cramping

The disease progresses over a three to five year period in most patients, but its progression varies from patient to patient. In some patients, the disease progresses rapidly over a year. Other ALS patients, like English physicist Stephen Hawking, can live for years with the disease.

Eventually, the patient with ALS is paralyzed, and will usually die of respiratory failure. For more information about ALS, visit Baylor's MDA/ALS clinic website.