ALS: Genetic discoveries, hope for treatment

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rapidly progressive neurodegenerative disease. There is no treatment, and ALS is almost always fatal within three to five years of diagnosis. Recent discoveries about the genetic basis of the disease — including the identification by researchers at Mayo Clinic in Jacksonville, Florida, of a repeat expansion in the C9ORF72 gene — as well as novel stem cell therapies offer new paths for developing treatments.

"What makes the chromosome 9 finding so exciting is that it helps explain a relatively large percentage of patients who have ALS," says Rosa Rademakers, Ph.D., who directs the Frontotemporal Dementia and Related Disorders Laboratory at Mayo Clinic's campus in Florida. "If therapies can be developed based on this finding, then a significant group of patients can be helped."

At Mayo Clinic in Rochester, Minnesota, researchers are conducting a clinical trial of stem cell therapy for ALS. Although the safety trial appears to be progressing well, efficacy hasn't yet been measured.

"I am optimistic about stem cell therapy; it is one of the more promising approaches we have right now for ALS," says Nathan P. Staff, M.D., Ph.D., a neurology consultant at Mayo Clinic's campus in Minnesota. "However, in contrast to the explosion of progress in the science behind what causes ALS, treatment strategies remain much more challenging."

Clumps of RNA

The C9ORF72 repeat expression is an unusual mutation. "This piece of RNA consists of six base pairs that, in normal individuals, are repeated three or four times. Individuals with the mutation have hundreds or thousands of repeated copies," Dr. Rademakers says. "These large aggregates of RNA form clumps in the nucleus of cells. The clumps attract other binding proteins, and as a result, the cell is misregulated."

The mutation is present in about 30 percent of people with familial ALS and 5 percent of sporadic ALS cases — as well as in 25 percent of people with familial frontotemporal dementia (FTD). "Increasingly, we realize that ALS and FTD may be two ends of a spectrum," Dr. Rademakers says. "A fair number of patients with ALS have symptoms of FTD, and vice versa. In post-mortem studies, we see the same disease protein deposited in the brains of people with FTD and spinal cords of people with ALS."

The clinical manifestations of the C9ORF72 mutation are correspondingly diverse. "Patients can present with memory problems and receive a diagnosis of Alzheimer's disease. Or they might undergo personality changes and have a diagnosis of bipolar disorder," Dr. Rademakers says. "The age of disease onset also varies. There are even individuals who live into their 70s and never develop symptoms."

These variations suggest that unknown modifying factors are at work. "We are very interested in identifying the genetic modifying factors that can determine whether someone gets ALS or FTD, and at an earlier or later age," Dr. Rademakers says. Current efforts focus on whether known genetic risk factors for FTD and ALS — for example, the ATXN2 mutation associated with ALS — may be responsible for determining when and if people with the C9ORF72 mutation develop disease, and which disease they develop.

Seeking biomarkers

In addition to forming clumps that disrupt cell function, abnormal C9ORF72 RNA creates toxic peptides. Based on that finding, Dr. Rademakers is working with Leonard Petrucelli, Ph.D., director of the Neurodegenerative Diseases Laboratory at Mayo Clinic's campus in Florida, to identify a biomarker for ALS. Work is also underway to identify additional genetic causes of ALS. One invaluable resource is the brain bank for neurodegenerative disorders at Mayo Clinic's campus in Florida, which has more than 5,000 brains, including 50 with the C9ORF72 repeat expansion.

"ALS is even more complicated than we thought," Dr. Rademakers says. "At least 50 percent of our familial cases and even more of our sporadic cases remain unexplained by the C9ORF72 repeat expression. There are definitely more genes involved."

Stem cell therapy safety trial

The stem cell therapy in clinical trial at Mayo Clinic's campus in Minnesota was developed in the Regenerative Neurobiology Laboratory, under the direction of Anthony J. Windebank, M.D. The treatment uses intrathecal autologous fat-derived mesenchymal stem cells. Eventually, the researchers hope to show that the re-engineered stem cells can deliver neural growth factors to patients, promoting nerve regeneration.

The dose-escalation safety trial involves 27 patients and is nearly complete. Treatment has been generally well-tolerated, with reported mild adverse events that are not likely related to treatment. No patients have developed progressive weakness worse than that expected with ALS.

Although some patients in the trial report changes in spasticity and muscle twitching and a perceived slowing of disease progression, "the placebo effect can be very strong in these studies," Dr. Staff says. Efficacy trials might start next year.

One possible benefit of stem cell therapy is its potential to act on multiple etiologic factors in ALS. "The neuroprotection offered by stem cell therapy is not a one-drug, one-target sort of approach. The stem cells likely are changing the immune system a little bit, and the growth factors that are released can have local effects," Dr. Staff says. "We are still far from an ability to halt ALS entirely. But I am hopeful that the molecular studies underway will hasten that."

For more information

A dose-escalation safety trial for intrathecal autologous mesenchymal stem cell therapy in amyotrophic lateral sclerosis. Mayo Clinic.

April 21, 2015