Amyotrophic lateral sclerosis is a rare, neurological disease that develops due to a loss of nerve cells (known as motor neurons) that control voluntary muscle movements such as walking, speaking and eating.
Currently, there is no cure for the disease. However, there is intense, cutting-edge research being conducted all around the world to find the cause and cure of ALS.
This article outlines some of the major areas of research that are being focus on by ALS researchers.
Patients with ALS have been shown to have high levels of a compound called glutamate, which is toxic when present in excess. Astrocytes are a type of nerve cell whose function it is clear glutamate away from the area around motor neurons.
The lack of glutamate clearance is likely the result of defects within astrocytes. Hence, researchers have been conducting studies on astrocytes to find a potential treatment method for ALS. Here are the results of some studies that have been conducted on astrocytes:
- Astrocytes that demonstrate an impairment in clearance of glutamate cause toxicity, which leads to degeneration of nerve cells in several models of ALS.
- Treating astrocytes in a mouse model of ALS can lead to a delay in onset of the disease as well as extend survival.
- Toxicity from astrocytes that causes damage to motor neurons was found to depend on the presence of particular types of mutations in astrocytes.
- Studies have shown that a protein called EAAT2 is not as efficient at clearing glutamate in patients with ALS compared to controls.
- Studies have found other factors that may increase the potency of glutamate in ALS patients.
At this point, researchers are working to further understand how astrocytes are involved in ALS and developing therapies to target them. Currently, the FDA has approved riluzole (Rilutek), which is a drug that is thought to interfere with action of glutamate. Studies are underway to develop more therapeutics that can attack this pathway.
It is well known that mutations within specific genes, such as SOD1, C9OR72, TDP43 and FUS, lead to the genetic or inherited forms of ALS. Furthermore, several studies have found other genetic mutations that contribute to rarer forms of ALS.
Scientists believe that there are likely genetic causes that can make a person more susceptible to developing sporadic ALS, which is the non-inherited form of ALS. In order to address this gap in knowledge, researchers have been conducting wide scale genomic studies:
- Gene association studies have shown that there two DNA sequences on chromosome 9 and one on chromosome 19 that are significantly different in people with ALS compared to healthy patients.
- One study found that there are expansions with the gene for ataxin 2 in 43% of patients with ALS and 14% of normal patients. Thus, ataxin 2 gene expansion can lead to a higher risk in developing of ALS.
- Drugs called antisense oligonucleotides have shown to help block defective SOD1, one of the genes implicated in genetic ALS, and lead to higher survival rates for mouse models of the disease. This strategy can be used for different genes in the future.
Immune system suppression
Several years of research have indicated that the immune system plays an important role in ALS disease mechanisms:
- Several groups of researchers have shown that the immune system is overactive in animal models of ALS.
- Immune cells in the central nervous system known as microglia have been implicated in the death of motor neurons in ALS.
- Pharmaceutical companies are testing whether blocking different parts of the immune system using experimental compounds can help treat ALS.
- Researchers are investigating whether CDP7657, an antibody that inhibits the immune response by targeting a protein called CD40L, can benefit patients with ALS.
- A phase 2 trial of fingolimod, a drug that suppresses the immune response, is underway for treatment of patients with ALS.
- Neuraltus Pharmaceutical is testing whether NP001, a drug that switches the immune system from damaging to protective mode, can benefit ALS patients through a phase 3 clinical trial in the future.
Patients with ALS that have a genetic mutation in the SOD1 gene tend to produce a SOD1 protein that is misfolded, and therefore, highly toxic. Researchers believe misfolded proteins may also be the underlying cause of sporadic ALS. These are the studies that have been and are being conducted on misfolded proteins in ALS:
- Studies have shown that other genes involved in genetic ALS, such as TDP43 and FUS, misfold and form toxic clumps in motor neurons.
- Proteins called chaperones help misfolded proteins fold into the correct shape. Hence, researchers are looking into increasing levels of chaperones through the use of experimental drugs called arimoclomol, which is being tested in a phase 2-3 clinical trial in ALS patients with SOD1 mutation.
- Antisense oligonucleotides can also stop misfolded SOD1 protein from being made, which is being tested in patients through clinical trials.
Mitochondria are organelles within cells that provide the cell with energy. It is thought that patients with ALS have an impairment in mitochondria function. The FDA has approved edaravone (Radicava) for the treatment of ALS, which functions to improve patients by relieving the effects of oxidative stress (which occurs a result of mitochondrial defects).
Currently, researchers are continuing to study mitochondrial impairment in patients with ALS in order to determine whether it’s a cause or consequence of motor neuron loss and whether reinstating mitochondrial function can help treat the disease.
Stem cells are cells that have the ability to differentiate (mature) into any type of cell in the body. Hence, researchers have been exploring their use as a replacement for the dying motor neurons in ALS patients. Researchers also use stem cells to study the progression of the disease and to screen for potential drug treatments.
- BrainStorm Cell Therapeutics has shown that its stem cell technology can help improve breathing, swallowing and muscle strength in four people with early-stage ALS. The company plans on continuing testing in phase 1-2 safety trial of adult stem cells.
- Neuralstem, another company, is testing its spinal cord stem cells in a phase 1 clinical trial. Results have indicated that it is safe for use. They conducted a Phase 2 study which showed that some patients responded to therapy. They are continuing to conduct further studies using this technology.
- Another company, Q Therapeutics, plans to test their unique stem cells in ALS patients which have been shown to slow down disease progression in rodent models of ALS.
Several research institutes and companies are continuing to try to cure ALS with stem cells.