October 2, 2003
QUICK SUMMARY: Researchers report that motor neuron cells involved in ALS can either be protected or damaged by surrounding non-neuronal cells. This discovery in mouse models supports the concept that using stem cell therapy to replace surrounding cells instead of motor neurons may be a feasible therapeutic approach in ALS that warrants further exploration.
In a study that holds promise for future stem cell therapy for ALS patients, researchers have discovered that non-neuronal cells surrounding nerve cells involved with ALS in mouse models play a major role in damaging motor neurons or sparing them from degeneration.
"This study underscores the importance of both the non-neuronal and neuronal cells in the disease process and highlights the possibility that restoring the surrounding non-neuronal cells may promote survival of the motor neurons," says Dr. Lucie Bruijn, ALSA science director and vice president. "This supports the idea that replacing the surrounding cells instead of the motor neurons may be a feasible therapeutic approach using stem cells and will be further explored."
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, causes paralysis and the premature death of the motor neurons that stimulate muscle contraction. The most common inherited form of ALS is caused by mutation in a gene (Cu-Zn-superoxide dismutase or SOD1) that is present in every cell in the body of those exhibiting this condition. However, scientists have observed that even though all cells make the mutant protein, it is only the motor neurons that are killed. This multi-center study was partly funded by The ALS Association's (ALSA) "Lou Gehrig Challenge: The Campaign to Cure ALS. The Lou Gehrig Challenge targets therapies and cure for ALS incorporating three research strategies: ALSA-initiated research, investigator-initiated research grants, and recruiting and cultivating new ALS researchers. The Cure ALS Advisory Committee, chaired by Tom Maniatis, Ph.D., Harvard University, identifies research to be funded.
"We've been given a new principle for extending survival, or perhaps overcoming ALS, based on how many healthy cells surround an ailing motor nerve cell," said Dr. Don Cleveland, Ph.D., the study's senior author. Cleveland also serves as chair of ALSA's Scientific Committee and is a recipient of support from the Lou Gehrig Challenge. "We're seeing a real-life metaphor; living in a bad environment can damage good cells. More importantly, restoring a better environment to 'bad' neurons by surrounding them with healthy neighbors can significantly lessen toxic effects. In some cases, having normal cells completely stops motor neuron death."
Investigators Robert H. Brown, Jr., M.D. D. Phil., Massachusetts General Hospital and Andrew McMahon, Ph.D., Harvard University, found that healthy surrounding cells slow the progression of ALS in the damaged neurons, providing a protective affect even when the nerve cells carry the mutant gene. Further, the researchers found the converse to be true. Genetically normal motor neurons were damaged when surrounded by mutant non-neuronal cells.
"The present study highlights how the exploitation of genetic models and the pooled efforts of distinct research teams can generate important new information that is critical for furthering our understanding of ALS, and ultimately the designing of appropriate therapeutic strategies," McMahon noted.
The general conclusion is that normal neurons are damaged by interactions with mutant neighbors, while good neighbors can protect mutant motor neurons from degeneration and death. The combined study report will be published Oct. 3, 2003 in the journal Science.
The researchers arrived at these conclusions by developing mouse models with a mixture of normal cells and cells with the ALS-causing mutant SOD1 gene. Previous studies have shown that mice with 100 percent mutant SOD1 develop ALS. Those with normal SOD1 never get the disease. In this new study, the "mixed-version" mice had extended survival with increased lifespans up to six months.
"Our study has strong implications for stem cell therapy," continued Cleveland. "We now believe delivery of normal, non-neuronal cells to spinal cords could be truly protective, even without replacement of a single motor neuron."
Without specific evidence of cause and effect, researchers believe that these healthy cells perform protective tasks such as nourishing motor neurons and scavenging environmental toxins. When damaged with mutant SOD1, these same cells fail in their protective role, contributing to the degeneration of the motor neurons.
"This study has exciting implications for stem cell replacement therapies in treatment of inherited ALS. However, more research is required to understand the relationship of non-neuronal cells and motor neurons," added Bruijn.
Questions and Answers:
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Where is stem cell therapy available now? Are there any stem cell trials enrolling patients?
Stem cell therapy for ALS is still in the laboratory research phase. While cell and animal work in ALS research laboratories is encouraging, there are several questions that must be answered before the necessary technology and understanding support initiating stem cell human clinical trials for people with ALS. For more information on stem cell research and ALS, click here.
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Why wouldn't researchers replace the motor neuron directly instead of its surrounding cells, even though they may have a beneficial effect on the neuron?
Two of the challenges to replacing dying motor neurons with stem cells are that the neurons have very long axons. It is not clear how long it might take for a stem cell to grow an axon that connects to a muscle fiber; and it is not known if the same mechanism that injures the neuron in ALS might have the same effect on the replacement stem cell. If cells surrounding the injured motor neuron can be replaced with stem cells so that they can possibly nourish, repair or protect the neuron, there is a potential that the neuron could be saved and not have to be replaced.
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Does this study provide hope for all people with ALS, or only those with the SOD1 mutation inherited form of ALS?
The research findings using the SOD1 mouse models of ALS helps increase the knowledge about both familial and sporadic ALS and is an important step in the discovery, development and testing of possible treatments. Since a mutation of the SOD1 gene is a proven cause of ALS, it is an excellent model for ALS research that benefits all people with this disease.
