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Patients' Fortitude Inspires Researchers to Seek Causes, Therapies for Lou Gehrig's Disease

At Cedars-Sinai, $17.8 million grant and research in stem cells, genetics and breathing-support are key elements in battle with ALS (amyotrophic lateral sclerosis)

Los Angeles - Nov. 1, 2012 – The instant Sal Silva’s bat struck the ball, he started his home run trot.

“I just crushed the ball and thought, ‘I’m going to have a good season,’” Silva says, reflecting on a game in March 2010. At 61, his off-season workouts were paying off as he played league games. But the homers didn’t keep coming. His right leg seemed too weak for him to power the ball over the fence. He started to stumble, too. Today, the former slugger is confined to a wheelchair – unable to raise his 215-pound frame even an inch.

In summer 2011, Silva came to Cedars-Sinai, where Evgeny Tsimerinov, MD, PhD, a clinician and researcher specializing in neuromuscular and neurological disorders, confirmed the diagnosis: Lou Gehrig's disease, amyotrophic lateral sclerosis. The disease attacks motor neurons in the brain and spinal cord – nerve cells that send electrical signals to muscle cells in the body. As the cells die, muscles grow weak and waste away.

“Sal is a very, very strong and ambitious person. Even being sick, he continued to work a long time, even crawling on his knees,” says Tsimerinov, associate director of the Clinical Neurophysiology Laboratory. He evaluates the former Walt Disney Company electrician every three months and says he admires his patient’s courage and tenacity for life.

The shortened life expectancy (three to five years) and bleak outlook (total paralysis) that comes with a diagnosis of ALS are well known. Because most forms of the disease affect only muscle-controlling neurons, patients’ mental status and awareness usually remain as sharp as ever. No cure exists, not even an effective treatment. But Cedars-Sinai doctors and scientists are advancing research and therapies to someday offer new options on ALS, inspired by the fortitude of patients like Silva.

The researchers recently were awarded a $17.8 million grant from the California Institute for Regenerative Medicine to study stem cell treatments to stop or slow the progression of the disease.

A new therapy involving the implantation of a diaphragmatic pacemaker to support breathing in the disease’s later stages – may prove to keep patients more comfortable.

Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute, who has studied the disease for a decade, calls ALS “a horrific disease, a nightmare that often affects healthy young people. We have to do something about it.”

When Svendsen and Patrick D. Lyden, MD, chair of the Department of Neurology, joined Cedars-Sinai in 2009, they identified ALS as a top clinical and research priority. The recruitment this year of Robert H. Baloh, MD, PhD, director of the Neuromuscular Division and the ALS Program, cemented Cedars-Sinai’s position as one of the most comprehensive ALS teams in California.

The researchers study the disease’s molecular and genetic mechanisms and work to engineer stem cells in the lab in a way that they hope may lead to a cure. That’s the longer goal. Today, with the CIRM grant, they are piggybacking a protein onto stem cells they hope will slow or stop disease progression.

A study currently in the planning stage will be based on nervous system stem cells derived from human tissue. Working with colleagues at City of Hope, researchers will expand these cells in Petri dishes for up to 40 weeks, making 50 billion cells per dish. These cells alone, when implanted into the spinal cords of laboratory rat models of ALS, turn into support cells called astrocytes and slow degeneration of dying motor neurons.  

Svendsen’s group then adds the next step, engineering the stem cells to make a protein, GDNF, that also protects neurons. The hope is that these stem cells will act like Trojan horses, releasing the protein next to the dying motor neurons inside the spinal cord.

In about two to three years from now, the researchers will seek permission from the Food and Drug Administration to test this experimental therapy in humans. “To our knowledge, this will be the world’s first study using stem cells to deliver a drug that protects dying neurons for ALS,” says Svendsen, adding that CIRM funding will support the four-year process, set to end with an 18-month clinical trial at Cedars-Sinai, Emory University in Atlanta and California Pacific Medical Center in San Francisco.

With technology available through a core facility of the Regenerative Medicine Institute, Cedars-Sinai researchers also employ stem cells not as a way to treat the disease but as a tool to study it.

“We take cells from patients’ skin, turn them into motor neurons in a Petri dish and study why these cells are different from those in people who don’t have ALS. This enables us to test drugs in a dish as we look for better ways to treat people,” Baloh says. “This technology was not available even five years ago and is an example of how quickly research is moving in this field. I think we can equate the last five years of molecular and scientific knowledge of ALS with the previous 150.”

Doctors today can only follow the disease’s lead, providing care to maintain comfort as body systems are compromised. The ability to breathe is affected at some point in almost every case and patients must consider surgical insertion of a breathing tube for survival. But an implantable system cleared this year by the Food and Drug Administration for limited use stimulates the diaphragm muscle, drawing air into the lungs in a natural rhythm, possibly postponing the need for ventilator surgery.

Cedars-Sinai was the first West Coast site to routinely implant the diaphragmatic pacemaker in ALS patients and has become one of the nation’s leading centers. Tsimerinov will lead Cedars-Sinai’s part of a multicenter Phase II trial that will continue to study the system’s effectiveness and safety.

Baloh notes that working at the thin line between basic research and patient trials helps clinicians and researchers maintain perspective. “I sometimes have scientists from the lab come to the clinic with me to see patients. Young scientists get really excited about basic research when they see why they’re doing what they do,” he says.