Unraveling the Mysteries of ALS
Can we prevent ALS before it starts?
Amyotrophic lateral sclerosis, also known as ALS, causes a breakdown of nerve cells in the spinal cord and brain. It’s often called “Lou Gehrig’s disease,” after the famous baseball player who passed away from the disease.
Loss of nerves due to ALS leads to progressive muscle weakness over time. Typically, it affects the arms, legs, and muscles that control talking, chewing, swallowing, and breathing.
Unfortunately, there is no cure yet.
People with ALS need to work closely with their physicians to manage the disease.
On a recent Inside U Miami Medicine podcast, Michael Benatar, M.D., Ph.D., chief of the University of Miami Health System’s Neuromuscular Division and executive director of the University of Miami ALS Center discussed how research is finding new ways to detect and treat ALS before symptoms appear. Dr. Benatar, the Walter Bradley Chair in ALS Research and a professor of neurology at the Miller School of Medicine, as well as Joanne Wuu, associate director for research at the ALS Center, are driving the research.
Because ALS is a complex disease, patients at the ALS Center receive care from a multidisciplinary team. Depending on each patient’s individual needs, this team may include a neurologist, nurse, physical, occupational, and speech therapists, as well as a respiratory therapist, nutritionist, psychologist, and social worker. By combining disciplines in one clinic, patients receive comprehensive care, which improves their quality of life and prolongs survival.
ALS has an ‘incubation period’.
“Part of what got me interested in studying this disease,” Dr. Benatar says, “is the concern that we bring treatments to bear too late in the course of the disease.
“The reasons for the delays in initiating treatment are manifold. Like many infections, ALS has an ‘incubation period’ where the disease is present without overt symptoms. Then, when symptoms do emerge, they may not immediately lead the patient or their physician to suspect ALS.
“In fact, in the U.S., the delay from symptom onset to diagnosis is about a year. It’s even longer before people get into an experimental trial to try a new drug. These factors combined can mean that treatments often start years after the disease begins. This is like trying to treat cancer when it is metastatic (when cancer cells spread beyond the original site). Treatments are more likely to be effective when we intervene early.”
To facilitate understanding of the earliest manifestations of disease, Dr. Benatar studies people who have an elevated genetic risk for ALS and a related disorder known as frontotemporal dementia (FTD).
This research helps identify “markers that tell us which people will develop the disease and when, and if there is an opportunity for early therapeutic intervention, perhaps even disease prevention.”
In most patients with ALS, the cause is not known.
However, in about 15% of patients, physicians can identify a genetic reason for the disease. The most common genetic cause of ALS is a “repeat expansion” in a gene known as C9orf72. Pathological variants in the SOD1 gene are another cause of ALS and are responsible for about 2% of cases. Notably, a genetic cause of the disease may be found both when there is a family history of the disease (familial ALS) and even when there’s no family history (sporadic ALS).
The bottom line is that “there may be a genetic cause of ALS even when there isn’t a family history,” says Dr. Benatar. Everything, however, is not explained by genetics. Aging and environmental exposures also play a role, even though these are much less well understood.
Understanding the biology that causes ALS offers clues to a promising therapy.
ALS, like many other neurodegenerative diseases, is characterized by the accumulation of “misfolded proteins”.
What is a misfolded protein?
Protein misfolding occurs when proteins take on an incorrect shape, which can impair their function and contribute to the development of diseases.
Pathogenic variants in the SOD1 gene, for example, lead to the production of an SOD1 protein that is prone to misfolding and is toxic to nerve cells.
To illustrate this idea, Dr. Benatar says, “Imagine you’re filing papers in a file cabinet. It’s easy when they’re straight. They file neatly. But if you crumple them up and try to file them, that filing system is going to be a mess.” Cleaning up misfolded proteins is one important approach to treating ALS and other neurodegenerative diseases.
Antisense oligonucleotides (ASOs) have emerged as therapies for patients with a range of neurological diseases. When injected into the spinal fluid, the ASO lowers the level of SOD1 protein, which reduces the amount of misfolded SOD1 proteins and the toxic effects in the nerve cells. The FDA recently approved a SOD1 ASO for treating patients with SOD1 ALS.
What are neurofilaments?
Neurofilaments are structural components of nerve cells that are released in the cerebrospinal fluid and blood when nerve cells deteriorate. Dr. Benatar and Ms. Wuu’s work has been integral to the field’s understanding of how neurofilaments might help advance therapy development.
One of Dr. Benatar’s discoveries was that neurofilaments in blood increase 6 to 12 months before the appearance of clinical signs of the disease in people who have SOD1 pathogenic variants associated with a rapidly progressive form of ALS.
“The discovery was critical to advancing the goal of ALS prevention. It gave us a tool to identify those people most likely to develop ALS in the short term. We could then target this group of individuals for a prevention trial using the SOD1 ASO,” Dr. Benatar says.
It’s better to treat people, Dr. Benatar says, closer to when they begin to develop the disease. For that reason, monitoring their neurofilament levels helps improve the timing and efficacy of treatment.
Dr. Benatar gives an example of a patient with high cholesterol.
A doctor doesn’t have to wait until the patient has a heart attack or stroke; if their cholesterol drops in response to medication, the doctor knows the drug is working.
“When neurofilament levels are high, but they go down when we give you an experimental treatment, that’s a good sign the drug is working,” Dr. Benatar says.
The ATLAS study
Dr. Benatar is also testing a new medication in partnership with a biotechnology company. They are studying asymptomatic people who have the SOD1 mutation associated with a very aggressive form of ALS.
“We monitor the neurofilament levels in their blood monthly, over time. When their levels go up, if there’s still no sign of disease, they either get a medication or placebo, and we continue monitoring until they do or do not develop the disease. If they develop ALS, they are given the active medication. This design ensures that the people in the trial never receive the active medication later than the time at which they first develop clinically manifest ALS.”
The ATLAS trial hopes to answer three questions.
- First, how effective is treatment with a SOD1 ASO when given at a time when neurofilament levels rise but before symptoms appear?
- Second, how effective is the SOD1 ASO when started at the time symptoms first appear?
- Finally, what is the comparative effectiveness of the SOD1 ASO when started at this earlier time point, compared to those who first received the gene therapy once the disease was already well established?
The idea of prevention represents a radical change in the treatment of ALS and other neurodegenerative diseases.
“If successful, similar approaches might be used in other forms of ALS as promising therapeutic candidates emerge,” Dr. Benatar says. Through the ongoing Pre-fALS study, led by Dr. Benatar and Ms. Wuu, the researchers are laying the foundation for future prevention trials.
We are making real progress in understanding the disease. And meaningful therapies will follow. For patients, there’s hope in participating in research.
Michael Benatar, M.D.
While the disease and the research behind it are complex, the ALS Center staff are motivated by their patients. “We’ve long believed that everything we do is on behalf of patients,” Dr. Benatar says.
Learn more about the center’s active studies.
Nancy Moreland is a regular contributor to the UHealth Collective. She has written for several major health care systems and the CDC. Her writing also appears in the Chicago Tribune and U.S. News & World Report.
Listen to the full podcast.
This article was adapted from the Inside U Miami Medicine podcast and was medically reviewed by
Dr. Benatar.
Tags: ALS biomarkers, ALS early detection, Dr. Michael Benatar, Neurodegenerative disease research
