Amyotrophic Lateral Sclerosis (ALS)

Symptoms, Diagnosis and Treatment
What causes ALS?
Can Stem Cells Help?
Looking to the Future
Canada
Links

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that is otherwise known as Lou Gehrig’s disease in North America and motor neuron disease (MND) in Australia and the United Kingdom. Although it occurs rarely, ALS is a mystifying and devastating illness.

ALS attacks motor neurons – the nerve cells in the brain and spinal cord that cause contractions in muscles and secretions from glands and organs and therefore control most of the body’s functions. In ALS, the neurons slowly waste away. They become unable to transmit signals that enable actions such as eating, speaking, walking and even breathing. The disease affects the entire body, usually causing death within 3-5 years.

The incidence of ALS is about equal to multiple sclerosis, but it is the most common cause of neurological death. About 3000 people live with ALS in Canada. It is most prevalent in males between the ages of 40 and 70. Only 10 per cent of cases are due to a genetic defect (known as familial ALS); the majority of people suffer from sporadic ALS, which arises for no known reason and is unrelated to family history. There is currently no cure for familial or sporadic ALS.

Symptoms, Diagnosis and Treatment

The nerves of the human body branch out from the spinal cord and contain central nervous system cells called motor neurons. These cells provide both sensory input to the brain and convey instructions to the muscles, glands and organs. Motor neurons can be as long as one meter, with a protective myelin sheath protecting the elongated body of the cell called the axon. In ALS, for reasons not yet clear, motor neurons degenerate and die. This interrupts the transmission of information between the muscles and the nerve cells leading to muscular weakness (atrophy) and uncontrolled movement.

ALS is not reversible because it attacks cells in the central nervous system (motor neurons), which lack the capacity to regenerate. In contrast, sensory neurons contain Schwann cells, which act like stem cells and can regenerate damaged nerve fibre.

Symptoms are usually subtle at the beginning and can be mistaken for other neuron-muscular disorders, such as Parkinson’s or MS. While certain drugs and exercise can strengthen wasted muscles, current treatments only delay the progression of the disease and alleviate symptoms. Within a relatively short time, controlling the muscles in the limbs, neck, face and torso becomes more difficult. A person can experience clumsiness and unsteady gait, have muscle twitching and cramping and feel extreme fatigue. As the condition spreads, the entire body becomes paralyzed. Cognitive functions may or may not be affected. The disease proves fatal when the muscles responsible for breathing and swallowing shut down.

Research on ALS is wide ranging in its search for a cause and a cure. Researchers are working to identify ALS biomarkers that would lead to the development of diagnostic tests to identify and track the disease. This would mean earlier treatment with the drug that works best for ALS in the early stages, rather than trying to piece together a clinical picture from vague symptoms that can be mistaken for other illnesses.

However, that still does not explain why it starts in the first place or how to reverse the damage.

What causes ALS?

Scientists are looking for clues that would explain why motor neurons begin to die. Some believe it to be a genetic instruction that interferes with normal cell behaviour. Recent genome-wide association studies have attempted to identify genes linked to sporadic ALS; however, many of the genes identified cannot be replicated in other studies, making it unlikely that there is a single gene linked to sporadic ALS. The cells may be lacking a vital neurotransmitter, a chemical that facilitates signaling between the brain and spinal cord. Inflammation, commonly found in ALS patient’s brains and spinal cords, appears to be involved in some way. Other scientists are looking at oxidation, nutritional and metabolic defects, mitochondrial damage, axonal transport and abnormal accumulation of proteins for possible answers.

There are other baffling questions: Are there similarities with Alzheimer’s, Parkinson’s and Huntington’s diseases, where an overabundance of abnormal proteins appears to create a toxic environment that causes nerve cells to die? And why are other nerve cells spared in ALS?

Previously, scientists believed that this disease did not affect nerve cells that enable other functions of the central nervous system, such as hearing, sight, thinking, learning and memory. However, recent discoveries have shown that cognitive impairment in the region of the brain responsible for decision-making, personality and speech does occur in some cases. The hunt is now on for the “molecular signature” of cognitive impairment in ALS as a symptom that might lead to early detection.

A small number of scientists are also focusing on the mechanism that governs cell death (apoptosis) in the hope of interfering with the relentless progression of the disease. An important discovery is that after the nerve dies, the “scaffolding” of the connection with the muscles and organs remains for some time. This leads them to hope that transplanted neural stem cells can graft onto existing nerve pathways and regenerate the nerves.

Can Stem Cells Help?

While the best scenario is to prevent the disease in the first place by understanding its cause, stem cell scientists are focusing on how to stop ALS once it begins and how to restore nerve function once lost.

Understanding the disease
Stem cells are key to research into early stages of motor neuron development and in understanding how the complex nerve pathways are established. Scientists can now recreate the conditions of early development using embryonic stem cells and instruct the stem cells to differentiate into neural cells, and then into motor neurons by manipulating the growth factors in the laboratory culture.

In order to understand what causes motor neurons to die, stem cell researchers are trying to create large quantities of motor neurons from human embryonic stem cells. However, since neuron fibres, or axons, are as long as one metre, and take time to grow, the logistics are considerable. Scientists can then test at what point in their evolution transplantation is feasible and effective to promote the replacement of motor neurons.

Many variables remain unclear in understanding possible treatment of ALS. When is the best time to transplant new cells, the best site to inject these new cells, and how to ensure the newly injected motor neurons know which muscle cell to connect to are some of the most pressing. Furthermore, without understanding why motor neurons die in the first place, transplanted neurons might be affected by the same disease process. These are all challenges that are being addressed by current research.

A giant leap forward
The groundbreaking discovery of induced pluripotent stem cells (iPS) in 2007 enabled ALS researchers at Harvard and Columbia Universities to take a giant leap in 2008 with a technique that may be applied to many other diseases. The researchers used an iPS cell technology to transform an ALS patient’s own skin cells into motor neurons. They “reprogrammed” the skin cells into a pluripotent state by introducing four genes into the cells, causing them to revert to embryonic stem-cell status. These pluripotent cells were then coaxed to become motor neurons. Using this approach, scientists were able to generate motors neurons that were genetically identical to a patient’s own neurons, in this case a patient who had the genetic form of ALS. Using the motor neurons created from ALS patients, scientists may now be able to study the course of the disease in the laboratory using a patient’s own cells and decode what is triggering cell death. However, there remain questions surrounding whether motor neurons generated in this way show differences to motor neurons generated from healthy individuals.

By replicating the disease in the laboratory, researchers are beginning to understand the critical role of glial cells, which are specialized cells that support motor neurons. The big question that has been stumping scientists for years is whether the disease is intrinsic in the motor neurons themselves, or is something else killing them – are they being “murdered” or “committing suicide?” There is growing evidence that not only are motor neurons key in the disease process, but also the surrounding glial cells.

Beyond understanding what causes the disease, this new strategy has implications for all of stem cell science in delivering on the promise of multiplying the diseased cells that have been derived from the patient to test which drugs might be effective for treatment.

Treating the disease
Besides drug discovery, there appear to be two possible ways to use stem cells to treat ALS: by transplanting them into the spinal cord to restore and regenerate tissue, and by using them as carriers for therapeutic drugs that are delivered to the sites of injured nerves.

Scientists are examining how the hippocampus of the normal adult brain continues to generate nerve cells throughout life and integrate them into existing circuits. There is ongoing research to determine whether endogenous stem cells in the brain and spinal cord can be stimulated to generate neurons.

The prospect of neural cell transplantation has shown some progress of late. Recent studies have shown that such treatment restores functionality in rats and delays progression of the disease. It appears that the grafted stem cells develop into neurons that can make substantial connections with existing neurons.

Scientists at Johns Hopkins University have used stem cells to restore the circuitry – stretching from the spinal cord to targeted muscles – in dogs paralyzed by ALS. Now, experiments are focusing on where to transplant these cells along the spinal cord for maximum benefit to outlying muscles.

In addition, it may be possible for stem cells to slow down the progression of the disease, since they tend to migrate to the damaged nerves. This ability of stem cells to hone in on the site of injury may also be useful for delivering therapeutic drugs to just the place they are needed. Furthermore, it is encouraging to scientists that transplanted cells do not appear to be affected by cells degenerating around them, and indeed healthy stem cells may benefit the glial cells that support motor neurons.

Most recently, scientists at Johns Hopkins University found that not only can transplanted human stem cells mature into neurons when injected into rats, but that in some cases, these cells connected with the rats’ own spinal cord cells, allowing nerve repair. This study challenges the long-standing belief that the spinal cord is incapable of repairing itself. The next step is to prove that these connections can transmit the nerve signals sufficiently to allow the affected muscle to function.

Looking to the Future

There are research teams in the USA, Canada, the United Kingdom, Israel, Germany and China that are considering how stem cells might be used to treat ALS. Some of this research is moving toward clinical trials.

For example, neural stem cells transplanted into the spinal cord have been found to migrate to precisely those sites that require healing and reconnection of the circuitry. This important finding is encouraging research groups in the US to explore using stem cells to deliver novel therapeutic drugs to support dying neurons.

It appears to be necessary to transplant cells at multiple sites along the spinal cord because benefits are localized. As yet, the muscles that support breathing have not responded readily to stem cell transplantation. To bring these advances and the technology for neural transplantation into clinical trials requires that scientists overcome these challenges and be able to create a dependable source of neural stem cells.

California Stem Cells Inc. recently announced that it now has the capacity to generate billions of motor neurons for cell replacement therapy. Another US-based company, Neuralstem, recently began the first clinical trials for ALS to test the safety and feasibility of both their neural stems cells and the method of delivering them to the spinal cord. The aim of their experimental procedure is to slow down the degenerative process.

Clinical trials have recently completed at Peking University to test G-CSF, a growth factor that when injected activates protective pathways and helps stimulate the brain to heal itself – an approach that, if successful, has implications for the treatment of many neurodegenerative conditions, including ALS.

The animal models for ALS allow for continuation of basic research and screening of drugs that are already FDA-approved for other illnesses. In the meantime, research groups and drug development companies in the USA are forming partnerships for a more aggressive approach to ALS therapeutics based on stem cell technology.

Canada

Scientists at the University of Toronto’s Centre for Research in Neurodegenerative Diseases and the ALS Clinic in Vancouver are the forefront of researching a stem cell-based treatment for ALS.

Whether treatments harm or help may depend on the growth factors that are used to stimulate production of stem cells. One Vancouver study examined treatment with G-CSF and found that bone-marrow stem cells became activated and circulated in the body with no adverse effects to patients – a promising approach to slow the progression of the disease.

A second study is in phase 1 clinical trials to test whether a treatment with a different growth factor (G-DSF) is toxic: it may also mobilize immune cells called microglial cells, which are implicated in ALS. Either microglial cells can help a neuron that is sick or dying to recover, or they can kill the neuron to limit the damage and prevent the spread of illness. For some reason, ALS causes microglia to kill off neighbouring healthy neuron cells as well as the sick ones.

Scientists in British Columbia are trying to track the suspect microglia to discover how they spread the disease. Since these cells are very good at getting at the disease area, the scientists think they might be used for delivering growth factors known to support neurons and keep them alive.

In terms of cell transplantation trials with humans, the ability to direct the development of stem cells into motor neurons (rather than some other kind of cell) and to coax them to migrate to the places that need repair is necessary before clinical trials are envisioned.

The disease mechanisms in all neurogenerative diseases can be very similar, so advances in one field affects many fields. The collaborative model for scientific research lends momentum and direction to research that builds on transferable knowledge and new technology. Scientists are far more hopeful for a cure for ALS now than they were even five years ago.