November 19, 2018
By closely following the relatives of some individuals with ALS, researchers at Columbia’s Eleanor and Lou Gehrig ALS Center hope to find ways to detect the disease before symptoms arise, allowing for early therapeutic intervention.
Currently, at the time ALS is diagnosed, individuals have already suffered significant, irreversible damage to motor neurons in the brain and spinal cord.
If ALS could be detected before symptoms become apparent, researchers believe that treatment has a better chance of preventing extensive neuron loss, or at least slowing the progression of the disease.
ALS Families Project
Of the estimated 15,000 individuals with amyotrophic lateral sclerosis, or ALS, in the United States, about 10 percent to 15 percent have a mutation in one of more than 30 genes associated with ALS.
Relatives of these individuals–if they carry the same mutation–have a high risk of developing the disease.
Columbia’s ALS Families Project identifies these asymptomatic relatives and will follow them until symptoms appear. (Early symptoms of ALS, or Lou Gehrig’s disease, can include clumsiness, gait imbalance, muscle weakness and wasting, and slurring of speech.)
“Studying the relatives of these patients provides the opportunity to understand the earliest steps in the onset of ALS, which may occur months or even years before obvious symptoms appear,” says Neil Shneider, MD, PhD, associate professor of neurology at Columbia University’s Vagelos College of Physicians and Surgeons. Shneider directs the program with Matthew Harms, MD, associate professor of neurology and a member of Columbia’s Institute for Genomic Medicine, and Elizabeth Harrington, CGC, genetic counselor at the Eleanor and Lou Gehrig ALS Center.
“By closely following relatives who carry the same mutation,” Shneider says, “we hope to develop markers of ALS that can guide our efforts to intervene early in the course of the disease.”
Mouse Models Can’t Answer These Questions
Symptom onset and disease progression vary widely in ALS, even between individuals who carry the same mutation or variants of the same gene. Some carriers never develop symptoms of the disease.
“We have good mouse models of ALS, but the truth is that mice are very different from humans in terms of symptom onset and rates of disease progression,” says Shneider. “The questions we are asking can only be answered by looking at people at high risk of developing ALS.”
“The vast majority of those with ALS do not have a family history of the disease, making early detection difficult, if not impossible,” adds Shneider. “We want to find out if early detection in those with familial ALS will also help us identify sporadic cases earlier.”
The Search for an ALS Biomarker
The program will perform DNA sequencing to look for subtle details in the genomes of study participants that could give a clearer indication of how and why the disease develops. Serial neurological exams, spinal fluid biopsies, electrophysiologic testing, and imaging tests will look for markers that presage symptom onset. (Free genetic counseling is also available to help participants decide whether to learn their carrier status.)
“One thing we are hoping to develop is a method for imaging the ALS brain,” says Shneider. “Most patients have a normal brain MRI, but it could be that we aren’t looking with the right type of imaging equipment and analytics. Having a brain imaging marker would give clinicians something concrete to follow during the course of the disease, both for diagnostic and therapeutic purposes, similar to the way tau pathology, measured by PET, shows Alzheimer’s disease progression.”
Since its inception in October, the program has enrolled more than 12 pre-symptomatic carriers from New York City and elsewhere. Participants will come to Columbia once or twice a year for examination and testing. The program is expected to expand significantly in the next few years.
The ALS Families Project will share data with other academic and industry researchers who are looking for ALS biomarkers and developing new therapies, including gene therapies. “This project is something that can only be done at a center like ours, which has the infrastructure to perform precision medicine-based work, but we don’t plan to keep these valuable samples to ourselves,” Shneider says. “We hope the program will support industry’s effort to develop preventive treatments.” [read more]