Genetics Muscular Dystrophy / ALS

ALS: A new therapy may be in sight

New research makes a discovery that “suggests a clear approach for developing a potential therapy for ALS.”
mum and daughter in wheelchair laughing
New experiments may provide ‘great hope’ for people living with ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that affects a person’s motor neurons.

According to the National Institute of Neurological Disorders and Stroke (NINDS), people with ALS experience gradual paralysis, which often results in death from respiratory failure within 3–5 years. Approximately 10 percent of people who have the condition, however, go on to live for 10 years.

The NINDS also quote the Centers for Disease Control and Prevention’s (CDC) 2016 estimate that 14,000–15,000 people in the United States have the condition. ALS currently has no known cure.

The U.S. Food and Drug Administration (FDA) has only approved two drugs that slow down the disease, albeit modestly: riluzole and edaravone. Clinical trials have shown that riluzole extends survival by a few months, while edaravone improves the daily functioning of people with ALS.

Generally, however, individuals living with ALS mainly benefit from supportive or palliative care.

New research may help change these limited treatment options, as scientists have uncovered a gene which could serve as a new drug target.

Joseph Klim, a postdoctoral fellow in the Harvard Department of Stem Cell and Regenerative Biology in Cambridge, MA, is the first author of the new paper, which appears in the journal Nature Neuroscience.

‘Experiments provide great hope for patients’

Previous research has found that the protein TDP-43 aggregates in the neurons of people with ALS. Instead of remaining in the nucleus of these cells — as it would in a healthy neuron — in ALS, the protein leaves the nucleus and accumulates in the cell’s cytoplasm.

This discovery led researchers to believe that the neurons’ “trash-disposal” system was genetically faulty in a way that affected TDP-43, but they did not know which genes were responsible.

TDP-43 binds to RNA, which communicates the genetic information needed to activate a certain protein.

In this study, Klim and colleagues decided to investigate every type of RNA that the TDP-43 protein in human neurons regulates. They also genetically modified TDP-43 and studied the effects.

Using motor neurons created from human stem cells, the scientists decreased the TDP-43 protein and examined how gene expression changed as a result.

RNA sequencing revealed that Stathmin2 (STMN2), a gene that plays a key role in the growth and repair of neurons, changed significantly and consistently along with TDP-43.

“Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2, we could see how a motor neuron might begin to fail in ALS,” Klim explains.

Kevin Eggan, who is a professor of Stem Cell and Regenerative Biology at Harvard and the study’s corresponding author, explains how the scientists reached their results.

“With the discovery that our human stem cell model had predicted exactly what was happening in patients, [Klim] went on to test in this system whether fixing Stathmin2 could rescue the motor neuron degeneration in our dish caused by disturbing TDP-43.”

“In a beautiful series of experiments that I believe provide great hope for patients, he went on to show this was exactly the case: rescuing expression of Stathmin2 rescued motor neuron growth,” says Prof. Eggan.

Kim adds, “We discovered that when TDP-43 levels are diminished in the nucleus […], it becomes impossible for STMN2 to create a vital component for repairing or growing motor neuron axons.”

The researchers also analyzed human neurons that they obtained postmortem from people who had lived with ALS. These findings further replicated their stem cell results.

“These experiments point towards a clear path for testing whether repairing Stathmin2 in patients can slow or stop their disease,” says Prof. Eggan.

The discovery we have made suggests a clear approach for developing a potential therapy for ALS — one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease.”

Prof. Kevin Eggan

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