Use of Patients’ Brain Cells to understand Amyotrophic Lateral Sclerosis

To better understand amyotrophic lateral sclerosis (ALS), a research team at Johns Hopkins Medicine was able to transform skin cells from ALS and Lou Gehrig’s disease patients into brain cells affected by this severe condition. The researchers deposited the human-made cells derived from the study into the first public ALS cell library. The study was recently published in PLOS ONE.

The team used an engineering-genetic based method that makes adult skin cells convert into “pluripotent” cells, known as induced pluripotent stem cells, which are capable of taking the form of different cells found in other body parts. “We make brain cells out of the patient’s own skin,” said Jeffrey Rothstein, M.D., Ph.D., who directs the Brain Science Institute and the Robert Packard Center for ALS Research.

The research team led by Rothstein is the first to use these stem cells to generate the largest library of brain cell lines, created from about 20 patients with ALS caused by different genetic mutations. “These human cellular tools will serve as a platform to understand ALS and someday discover new drugs to treat our patients,” said Rothstein, senior author of the study.

In the United States, more than 30,000 people have ALS, and the condition appears to affect more men than women. Estimates indicate that one in every 500 deaths are because of ALS. Rothstein said, “So just about everyone is going to know a neighbor, friend or family member who will eventually succumb to this terrible disease.” There is no known cure for ALS and there is only one FDA-approved drug, riluzole, which may only add a year to a patient’s life span.

The researchers have been studying ALS from the past 25 year in animal models, Rothstein said, “But after 25 years, it has not led to the development of a drug that works in our patients.” Some drugs that where found to be effective in mice models were tested in Phase II clinical studies, however, failed in Phase III trials as the drugs were not effective in humans. “There has to be a set change in how we approach ALS,” Rothstein added.

Due to ethical constrains of the use of human brain tissue, the research team used induced pluripotent stem cells, a method that provides researchers with a tool to observe diseased human brain cells such as astroglia, nerve cells that play a crucial role in the progression of ALS. The team created a total of 22 patient-specific cell lines that had mutations associated with ALS. Then they deposited them in a cell library in order to be available to other researchers.

In the library there are cells of inherited ALS patients, which accounts for approximately 10% of ALS cases. They also created cells from sporadic ALS, which accounts for about 90-95% of ALS. They collected from patients genetic variants from both sporadic and inherited ALS forms and included to the library.

Many researchers have now used the cells from the library, and the trend is for the number of users to grow, according to Rothstein, who adds: “Now we have a real model for what’s wrong with my patients.”