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ALS: Amyotrophic Lateral Sclerosis


Intense research is being conducted in many areas related to ALS, from basic science seeking the roots of the disease, to therapy development to find effective treatments.

Since inception, MDA has dedicated over $344 million to ALS research and health care services. In the past five years alone, MDA has spent over $46 million toward ALS research.

Research into familial (running in families) forms of the disease also may have relevance for sporadic (nonfamilial) forms, as all ALS cases — regardless of the form — may present and develop along similar lines.

Many other medications and treatments are being tested for potential benefits in ALS. See Clinical Trials for details.

This section offers an overview and links to more information about ALS research targets and strategies, and research administration in ALS.

Additionally, there are many strategies currently in the pipeline for ALS drug development.


While some research teams have focused their attention on microglia, the nervous system's immune cells, others have focused more on astrocytes, a type of non-nerve glial cell that normally provides support to motor neurons and other cells in the nervous system. Among their roles is clearing away a potentially toxic compound calledglutamate from the area around nerve cells. ALS patients have been shown to have dysfunctional clearing of glutamate which is likely due to defects within astrocytes.

Investigators have shown that treating astrocytes alone can delay disease onset and extend survival in mice with a disease resembling ALS caused by mutations in the SOD1 gene.

In 2011, researchers showed that toxicity from astrocytes causes nerve cells to degenerate in new models for both inherited and noninherited forms of ALS.

Study results from two experiments reported in 2013 showed that astrocyte-associated harm to motor neurons may differ depending not only on whether the astrocytes carry a mutation, but on which mutation they carry as well.

Currently, there are many laboratories working to understand how astrocytes become dysfunctional in ALS and develop therapies targeting astrocytes for ALS patients.

Genetic contributions

Many genes, when mutated, can cause familial ALS. Among them are the SOD1 gene, the TDP43 gene and theFUS gene. In 2011, a specific mutation in the C9ORF72 gene was found to be the most common genetic cause of the disease identified so far. Defects in the C9ORF72 gene were also shown to cause another disease called frontotemporal dementia (FTD). Some patients with the gene defect develop ALS, some develop FTD, and some patients develop symptoms of both diseases. (See Causes/Inheritance.) Other genes shown to contribute to rare forms of ALS include ubiquilin 2, profilin 1, valosin-containing protein, alsin, senataxin, angiogenin, and optineurin. If someone with an ALS-causing gene mutation is the first in the family to show the disease, the disorder is classified as sporadic, since there is no family history. (This can happen when, for example, a parent carrying the ALS-causing mutation passes away of other causes before ALS develops but not before passing the mutation along to his or her children.)

However, research on the genetic factors that contribute to ALS, without necessarily causing it directly, is of great interest. Scientists suspect that a number of gene variants — probably in combination with other unknown factors — may increase susceptibility to sporadic ALS.

Several large gene association studies have been done comparing the DNA of people with and without ALS in hopes of uncovering genetic differences. These studies have pointed toward potential genetic targets for ALS research. For example, a large, multinational study to identify genetic risk factors associated with ALS found two DNA sequences on chromosomes 9 and one on chromosome 19 that are significantly different in people with and without the disease and may contribute to its development.

When scientists studied DNA from 915 people with ALS and 980 without the disease, they found expanded ataxin 2 genes in 43 (4.7 percent) of those with ALS and only 14 (1.4 percent) of those without it. They concluded that ataxin 2 expansions are significantly correlated with increased risk for developing ALS. Expanded ataxin 2 protein molecules appear to have toxic interactions with TDP43, another protein implicated in ALS, and blocking ataxin 2 interactions with TDP43 could become a new therapeutic avenue.

There are several approaches in development to treat genetic versions of ALS including familial ALS caused by SOD1 mutations. The strategy involves development of a drug called an antisense oligonucleotide which is able to block defective SOD1. This approach may also be useful for other types of ALS caused by different genes. 

Glutamate inhibition

In ALS, there is some evidence that excess amounts of the neurotransmitter glutamate accumulate in the spaces around a nerve cell after it has completed its signaling function, causing problems for nerve cells in the vicinity.

Normally, glutamate — a chemical transmitter of signals between nerve cells — is released by a sending neuron and docks on a receiving neuron. Once docked, it is quickly cleared away by glutamate transporter proteins, which are produced by neighboring cells in the nervous system called astrocytes. In ALS, something may go wrong with this glutamate clearance system. Some studies have suggested that, in ALS, a protein called EAAT2 may not be as efficient at clearing glutamate away from nerve cells as it should be. Other studies have suggested that a glutamate receptor, a docking site on the surface of motor neurons that receives glutamate, may be excessively permeable in this disease.

A drug specifically approved for the treatment of ALS by the U.S. Food and Drug Administration (FDA) is riluzole (Rilutek), which is believed to interfere with the action of glutamate.

Immune system involvement

There is a growing body of evidence that malfunction of the immune system is at least part of the ALS disease process. Research conducted at the ALS Therapy Development Institute (ALS TDI) and other labs has identified abnormal immune system overactivity in animal models of the disease, and ALS TDI investigators have observed it in blood samples from people with ALS.

It had been thought that motor neurons died alone in ALS. But, today, there is evidence that immune system cells in the nervous system called microglia are probably involved in their demise.

Blocking parts of the immune system is a strategy being pursued by ALS TDI researchers at ALS TDI. In 2011, the nonprofit biotech announced it would pursue testing experimental compounds in ALS mice that disrupt parts of the immune system. One, CDP7657, is an antibody fragment that inhibits the immune response by targeting a protein called CD40L. In 2013, ALS TDI launched a phase 2 trial of Gilenya (TDI 132, fingolimod) in ALS. Gilenya dampens the immune response and is approved by the FDA for the treatment of multiple sclerosis.

In addition, scientists at Neuraltus Pharmaceuticals are working on an experimental drug called NP001, which is designed to switch immune system cells from a damaging to a protective mode of action. In 2012, Neuraltus released the results from its phase 2 clinical trial in ALS patients that showed NP001 was safe and well-tolerated. Based on these results, the company is currently planning on taking the drug forward in a phase 3 trial.

Misfolded proteins

Cellular proteins normally fold only in certain ways shortly after they're produced. When folding goes wrong, the result may be a highly toxic protein. In 2010, researchers found that misfolded SOD1 protein, unaccompanied by an SOD1 gene mutation, could underlie at least some cases of sporadic ALS.

Other proteins besides SOD1 may misfold and contribute to the disease as well. For example, the TDP43 and FUS proteins appear to misfold and form clumps (aggregate) in ALS-affected motor neurons even when the genes for these proteins are normal.

Normally, proteins called chaperones help coax other proteins to fold into the correct shape. Therefore, some scientists are working on increasing levels of these chaperone proteins. An experimental drug called arimoclomolis being tried in SOD1-related familial ALS with this mechanism in mind. Currently, arimoclomol is being tested in a phase 2-3 clinical trial in familial ALS patients harboring defects in the SOD1 gene.

Another approach to targeting misfolded SOD1 is a type of molecule called an antisense oligonucleotide, which keeps toxic, misfolded SOD1 from being made. In 2012, the antisense-based drug ISIS-SOD1-Rx was found to be safe and well-tolerated in people with SOD1-related familial ALS in a phase 1 clinical trial. The drug was developed by Isis Pharmaceuticals with support from MDA. Work is underway to optimize the antisense oligonucleotide prior to further testing in ALS patients.

Mitochondrial factors

In ALS, the cellular "energy factories" called mitochondria malfunction, although it isn't clear exactly where in the chain of events of the ALS disease process this malfunction occurs.

When mitochondria malfunction, they may fail to produce the needed energy for cells, and they may leak toxic substances called reactive oxygen species, subjecting cells to a kind of poisoning known as oxidative stress.

The U.S. Food and Drug Administration on May 5, 2017, approved edaravone (brand name Radicava) for the treatment of ALS. Radicava is thought to work by relieving the effects of oxidative stress. Targeting this pathway could potentially preserve motor neuron health, which could in turn, keep muscles functional for a longer period of time. For more, see FDA Approves Radicava to Treat ALS and Questions and Answers About Newly FDA-Approved Radicava to Treat ALS.

Unfortunately, coenzyme Q10, which combats oxidative stress, was not found to be helpful in people with ALS, even at high doses. (Coenzyme Q10 is an antioxidant, which is a substance that helps clean up free radicals.)

MDA-supported researchers continue to study mitochondrial dysfunction in ALS, with an eye to determining whether it's a cause or a consequence of motor neuron loss and whether restoring mitochondrial function can alter the ALS disease course.

Stem cells

Stem cells can be thought of as cells that are in the very early stages of development, before they have become specialized (differentiated) to perform specific roles in tissues. They may be precursors to a specific cell types (such as muscle or nerve cells), or they may still retain pluripotency — the ability to develop into any of a number of different cell types.

In ALS, disease-affected stem cells are being used as models in which to study disease processes and screen potential therapies. For example, in 2011, researchers created a model of a type of ALS caused by mutations in the VAPB gene by causing skin cells from people with this form of the disease to revert to stem cells and then growing them in laboratory dishes.

Stem cells also are in development as cell-transplantation therapies. Theoretically, stem cells could be used to replace ALS-affected motor neurons; replace other types of cells, such as astrocytes; or release supportive proteins to help ailing nerve cells.

Early in 2012, the Israeli company BrainStorm Cell Therapeutics announced that its NurOwn stem cell technology appears safe and appears to have improved breathing, swallowing and muscle strength in four people with early-stage ALS, in a trial in Israel. In early 2013, BrainStorm, which plans to test its NurOwn stem cell technology in a trial in the United States in people with ALS, has advanced its phase 1-2 safety trial of adult stem cells to a phase 2a dose-escalating trial.

Another biotechnology company, Neuralstem reported in 2012 that its spinal cord stem cells, and the surgical technique used to transplant them, proved to be safe and well-tolerated in a phase 1 clinical trial in 12 people with ALS. This first U.S.-based trial of neural stem cells in ALS opened at the MDA/ALS Center at Emory University in January 2010. In 2014, Neuralstem announced topline results from their Phase 2 dose-escalation clinical trial which proved the cells were safe and that some of the patients may have responded to the therapy.

In addition to BrainStorm Cell Therapeutics and Neuralstem, another biotechnology company called Q Therapeutics announced that they have received approval by the FDA to test their unique stem cells in ALS patients. The stem cells are called glial-restricted progenitor cells and these cells have shown promise in slowing the disease progression in rodent models of ALS.

Many companies and institutions outside the United States (and a few inside) falsely advertise that they can cure ALS with stem cells. So far, there are no stem-cell-based treatments for ALS that are known to be effective at slowing ALS, although Neuralstem's technology appears to be safe so far. Some companies may not even be injecting stem cells. Other may be using stem cells that are too undifferentiated and can be dangerous, while others may be using cells that are too differentiated and are no longer able to join existing tissues. Bottom line: Advertised stem cell therapies should be approached with great caution.

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