ALS in the Strike Zone
It is a devastating neurological disease that takes the body hostage and then methodically destroys it while the mind stays painfully alert.
Lou Gehrig’s disease is still incurable and largely untreatable, but a stream of recent scientific breakthroughs in genetics, neuroscience, and regenerative medicine—plus the determination of committed researchers and physicians to slow or stop ALS’ brutal march—could be a game changer.
The instant Sal Silva’s bat struck the ball, he knew it was gone, and he started his home-run trot. “I just crushed the ball and thought, ‘I’m going to have a good season,’” he says, reflecting on a game in early 2010. At 61, his off-season workouts were paying off.
An electrician, Sal never missed work because of illness, but he gladly sacrificed some Fridays for his favorite pastime: swinging a bat and chasing down hits in the outfield for a local softball team that sometimes traveled to other states for long weekend tournaments.
But the homers stopped coming that season. His arms felt strong, and plenty of his hits found the gap in the outfield, but his right leg seemed too weak to power the ball over the fence. He started to stumble, too.
“When I was running, one foot would go and the other would not, and I would trip. That was when I really knew something was going on,” Sal says. He pauses and grips the arms of his wheelchair, shifting position to take pressure off his diaphragm.
For 40 years, his cheerful voice and easy laugh had mingled with the rattle of the toolbox he lugged around his workplace at The Walt Disney Company’s home office in Burbank. When his failing muscles began to endanger his life on the job, he consulted a neurologist. Then a second one.
Early hopes of a minor ailment quickly dimmed as increasing weakness and growing batteries of tests pointed toward amyotrophic lateral sclerosis (ALS)—also known as Lou Gehrig’s disease, named after the New York Yankees Hall of Famer who is believed to have succumbed to it in 1941. ALS 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 weaken and waste away. But because most forms of the disease only affect muscle-controlling neurons, mental status and awareness usually remain as sharp as ever.
“ALS may be the cruelest, most severe neurological disease,” says Clive Svendsen, PhD, director of the Cedars-Sinai Regenerative Medicine Institute, who has studied the disease for a decade. “It typically starts with muscle twitching and weakness in one limb. Within six months to a year, that limb will be totally paralyzed and floppy. The disease moves on to the next limb, usually the opposite one. It eventually affects breathing, and the only way to survive is to be attached to a ventilator, totally paralyzed in a wheelchair.”
ALS affects 30,000 to 50,000 Americans, a relatively small number when compared to other neurological diseases such as multiple sclerosis or Parkinson’s. But that statistic is deceiving.
“The risk is about the same as some other well-known neurological diseases, but ALS is a nasty killer,” says Dr. Svendsen. “There is, sadly, no accumulation of patients. ALS often strikes people in their 40s and 50s, in their most productive years. This is a horrific disease that breaks your heart. We really have to do something about it.”
That “something”—the much-needed treatment that has so far eluded the medical community—could consist of fixing a gene gone awry, stopping a domino-like series of events at the molecular level, or eliminating neuron-killing toxins that may somehow be infiltrating the brain and spinal cord. The fact is there may be no single cure because there may be no single cause. The long-term focus of regenerative medicine and scientists like Dr. Svendsen is to turn adult stem cells into healthy motor neurons or other cell types that can either replace defective ones or help the patient’s own cells survive and eventually cure the disease.
As Sal Silva’s mind began to absorb his new reality, he could not stop crying. He could not even say “ALS.” And he still cannot talk about those days without his voice wavering. With rare exceptions—Stephen Hawking, the famous theoretical physicist, was diagnosed at 21 and turned 70 last year—patients die within three to five years on average. And they usually spend that time battling depression, fatigue, muscle contractions, sleep disturbances, and loss of the ability to swallow, speak, or even breathe without medical intervention.
“Sal is one of our nicest patients. He is an incredibly strong and ambitious person. He continued to work a long time—even in his weakened state,” says Dr. Tsimerinov, who, because of the disease’s late stage of progression, evaluates Sal every three months.
Sal’s breathing is not yet seriously affected, but when that time comes, he may benefit from an implantable breathing-assist system recently approved by the Food and Drug Administration (FDA) for limited use. Cedars-Sinai was the first West Coast site to implant the device in ALS patients suffering from this uncommon disease (see sidebar).
Neurologist Evgeny Tsimerinov, MD, PhD, associate director of the Clinical Neurophysiology Laboratory, will lead Cedars-Sinai’s part of a multicenter Phase II trial that will continue studying the system’s effectiveness and safety. In the summer of 2011, about the time he finally had to retire from his job, Sal came to Dr. Tsimerinov, a clinician and researcher specializing in ALS and other neuromuscular and neurological disorders.
With no single test to detect ALS, doctors diagnose it by ruling out all other possibilities. It is rarely misdiagnosed, except in the earliest stages. “No other disease damages motor neurons in the brain and the spinal cord simultaneously without damaging other nearby systems. That’s the hallmark of ALS,” says Robert H. Baloh, MD, PhD, who studies the disease’s genetic and molecular makeup and is the director of Cedars-Sinai’s Neuromuscular Division and multidisciplinary ALS Program.
Still, Dr. Tsimerinov says clinicians always hope their initial suspicion is wrong. “We perform very thorough workups looking for any other condition that may mimic ALS, hoping to find a different disease that can be relieved with a medication or treatment.”
Gene defects and molecular abnormalities no doubt cause some cases of ALS, but researchers are also exploring environmental, occupational, developmental, and injury-related possibilities. Many neurologists who specialize in ALS say the disease affects a seemingly high number of athletes and people engaged in physical labor. Could brain trauma and concussions play a role? Could a high level of prenatal testosterone lead future ALS sufferers to engage in athletic endeavors and manual professions? Could some people be at high risk if they happen to choose occupations that trigger unknown genetic predispositions?
There’s more speculation than answers, but studies have found that U.S. veterans are nearly twice as likely as nonveterans to suffer from ALS. Exposure to toxic chemicals is a leading suspect. Sal served in the military from 1968 to 1970, spending a year in Vietnam, where he earned a Bronze Star, a Silver Star for gallantry, and a Purple Heart for shrapnel wounds. He now receives VA disability compensation.
The Department of Defense sets aside $20 million a year for ALS studies, and the National Institutes of Health, the ALS Association, and other organizations also fund research. But every passing day steals more of Sal’s strength, and his struggle against ALS becomes a greater effort just to hold on.
“The speed of progression is hard to predict, and the order varies, but with ALS, every motor system eventually will be involved,” says Dr. Baloh. “We provide interventions as body systems are compromised, mostly to try to maintain comfort and quality of life.”
Drs. Svendsen and Baloh and their research teams want nothing less than to cure ALS. Their current studies explore piggybacking a protein onto stem cells in the hope that it will slow or stop disease progression, and they expect to seek permission from the FDA in the next two to three years to test an experimental therapy in humans. The California Institute for Regenerative Medicine (CIRM) recently gave Cedars-Sinai a $17.8 million boost to the ambitious research that Dr. Svendsen said will include many departments—such as Neurology, chaired by Patrick D. Lyden, MD, and Neurosurgery, chaired by Keith L. Black, MD—and involve nurses, scientific staff, other professionals, and—if preclinical studies go well—patients.
“To our knowledge, this will be the world’s first ALS study using stem cells to deliver a drug that protects dying neurons,” says Dr. Svendsen, who hopes findings from this research may be applicable to other diseases that break down neurons, such as Parkinson’s, Huntington’s, macular degeneration, and even Alzheimer’s. He adds 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.
Dr. Svendsen, who has investigated a variety of regenerative medicine–based approaches to this and other diseases, is also conducting a new study that combines the power of two major technologies: stem cells and gene therapy. Working with colleagues at City of Hope, his team will expand the stem 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 animal models of ALS, turn into support cells called astrocytes and slow degeneration of dying motor neurons. Then Dr. Svendsen’s group adds the next important step.
“Using viruses, we engineer the stem cells to make a protein that also protects neurons. Now the stem cells act like Trojan horses, releasing the protein right inside the spinal cord, right next to the motor neurons that are dying,” he explains, noting that neurosurgeons at Cedars-Sinai play a vital role in these studies.
“We are one of very few groups working to implant cells into the spinal cord,” Dr. Svendsen says. “This requires a very specialized technique that not every neurosurgeon can perform, and our surgeons have worked during the past two years to perfect the procedures in animal models. It’s exciting because they will be using MRI-guided systems and minimally invasive techniques to get the cells into the spinal cord with amazing accuracy.”
“The discovery of these amazing cells earned Dr. Shinya Yamanaka, a senior investigator at the University of California, San Francisco, a share of the Nobel Prize in Medicine this year,” says Dr. Svendsen. “The cells are derived from a patient’s own skin samples and then ‘sent back in time’ to become ‘blank slate’ cells—very similar to embryonic stem cells. From there, they can be programmed into any cell of the human body. In theory, if made from an ALS patient being treated, iPSCs would be readily accepted—without the rejection issues of ‘foreign’ cells—and they could be banked for future use. If a patient gets ALS, we can make healthy nerve cells. If they get heart disease, we can make cardiac cells.”
In Dr. Baloh’s medical practice, he sees the ravages of disease. In his laboratory, he and his team of scientists search for underlying genetic mutations and molecular defects.
“Being at the edge of clinical research and basic science, we can plan our patient trials to address the right questions and measure the right things,” he says. “I sometimes have scientists from the lab come to the clinic with me to see patients. It’s great to see young scientists get really excited about basic research when they see why they’re doing what they do.”
Among their tools are stem cells, which, in this case, are designed not to cure the disease but to reproduce it in the lab. These studies use technology available through the Regenerative Medicine Institute’s iPSC Core Facility, which is developing new ways to grow adult stem cells into specific cells (brain, blood, bone, etc.) and then distribute them back to research scientists throughout Cedars-Sinai.
“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 do not have ALS. This enables us to test drugs in a dish as we look for better ways to treat people,” Dr. Baloh says. “The technology to do this 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. That’s the degree of speed at which we are increasing our understanding.”
Dr. Baloh’s research group was one of the first to discover that a mutation in a certain gene causes an inherited form of ALS and a type of dementia that can accompany the disease. Only one other ALS-related gene defect had previously been found, and although only 7 percent to 10 percent of ALS cases have a hereditary basis, scientists believe that by picking apart the building blocks of genetic forms, they can find universal clues. Scientists say they hope to find a cure but, in the case of ALS, finding a cure is not the only hope.
“If we can slow the disease process or halt it at an early stage so that remaining motor neurons stay alive, we can keep people stronger and help them maintain their independence,” Dr. Baloh says, adding that several recently completed major drug trials are in the data-analysis stage and that new medications could be approved within months. More drugs are in the pipeline, and the number of stem cell trials is expected to mushroom in coming months and years.
Today, Sal Silva is unable to raise his 215-pound frame even an inch in his wheelchair. He fell to the floor at home several months ago during a bed-to-chair transfer. His wife, Jeannette, struggled for an hour to get him back into his chair—a task made more difficult due to her own battle with fibromyalgia and a frozen shoulder. The couple, who have two adult children and three grandchildren, had planned to relax and travel after retiring in a few years. They have been by each other’s side since meeting in high school.
“Jeannette is still working,” says Sal, “and when she comes home, tired, she has to do things she never had to do before, the things I used to do—like take out the trash or change a light bulb. I feel bad that I can’t even help her with that.”
After a long pause, he adds: “I’m stuck in this chair, but if they could stop the disease now, I could live this way, you know? I’ve gotten very weak, but my mind is fine, I’m alive. But if I had to go much farther…” His voice trails off. “I used to walk my dogs every day. They miss that, and I miss little things that to others may seem unimportant. Some people say, ‘I’ll bet you really miss playing softball.’ I look at them and say, ‘No, I miss walking, and I really miss being able to play ping pong with my grandkids.’”
Like the physicians and scientists treating and studying the disease that afflicts him, Sal refuses to give up. When he no longer could count on his legs to patrol the outfield, he became a designated hitter.
“I would hit the ball and run to first, but I often would tumble because my gait was pretty bad,” Sal recalls. “In my last at-bat, which was in Georgia, I hit a ball into the gap and made it to third, even with my gait. That was it for me. I looked funny running, but I gave it all I had.”