A scientist’s fifteen-year journey to develop a stem cell-based therapy that could one day help ALS patients.

“Can stem cells help me, Clive?”

The sentence appeared slowly on a computer screen. Pauses separated each character as its author searched for the next one.

He used a device controlled by an eye muscle.

Jeff Kaufman, a Wisconsin man in his 40s, asked the question. ALS had left him completely paralyzed.

Clive Svendsen, PhD, listened. At the time, he worked as a scientist at the University of Wisconsin–Madison.

Stem cells and ALS

Svendsen wanted to understand how stem cells could help patients like Jeff.

Also called Lou Gehrig’s disease, ALS rapidly and aggressively damages the nervous system. Patients typically live two to four years after diagnosis.

ALS destroys nerve cells that send signals from the brain and spinal cord to muscles. Without those signals, muscles weaken and waste away.

Eventually, patients lose control of their bodies.

The United States has approved two ALS drugs: riluzole and edaravone, also known as Radicava.

However, these drugs slow disease progression by only a few months in some patients. No effective treatment currently stops or cures ALS.

Given this poor prognosis, Svendsen easily chose ALS as his research focus.

However, developing a treatment strategy challenged him.

“The problem with ALS is that we don’t know its cause,” he said. “About 10% of ALS cases are genetic, and we know some of the genes involved.

“However, 90% of cases occur sporadically.”

This knowledge gap makes it difficult for scientists to develop treatments for sporadic ALS. These cases have no known drug targets.

From Parkinson’s disease to ALS

Svendsen moved to Cedars-Sinai in Los Angeles in 2010. He now leads the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

He has studied ALS for the past 15 years.

Before focusing on ALS, Svendsen researched Parkinson’s disease, a chronic neurodegenerative disorder. Parkinson’s affects movement, balance, and speech.

Unlike people with ALS, people with Parkinson’s generally live longer and have more treatment options.

These treatments can ease their symptoms and improve their quality of life. As a result, people with Parkinson’s often have a better quality of life than people with ALS.

“I chose to work on ALS mainly because of its effects on families,” Svendsen explained. “People go from normal lives to rapid paralysis.”

Svendsen’s transition from Parkinson’s research to ALS also had a scientific basis.

He had studied GDNF, an important brain growth factor. The full name is glial cell line-derived neurotrophic factor.

Svendsen explored how GDNF could protect dopamine-producing neurons in people with Parkinson’s disease.

However, other research suggested that GDNF might protect motor neurons even more effectively.

ALS destroys these nerve cells.

With this knowledge, Svendsen and his team developed an experimental stem cell therapy for sporadic ALS.

They did not plan to replace the motor neurons that ALS destroyed.

Instead, Svendsen focused on transforming another type of brain cell: the astrocyte.

Rooting for the underdog

“I chose to work on ALS mainly because of its effects on families,” Svendsen explained. “People can go from normal lives to rapid paralysis.”

Svendsen’s shift from Parkinson’s research to ALS also had a scientific basis.

He had studied GDNF, an important growth factor in the brain. Its full name is glial cell line-derived neurotrophic factor.

Svendsen explored how GDNF could protect dopamine-producing neurons in people with Parkinson’s disease.

However, other research suggested that GDNF might protect motor neurons even more effectively.

ALS destroys these nerve cells.

Based on this finding, Svendsen and his team developed an experimental stem cell therapy for sporadic ALS.

They did not intend to replace the motor neurons that ALS destroys.

Instead, Svendsen focused on transforming another type of brain cell: the astrocyte.

“Although ALS clearly destroys motor neurons, it also harms the astrocytes surrounding them,” Svendsen said.

“Replacing a motor neuron presents a major challenge. The new neuron must grow a nerve fiber to the muscle.

“We could not even achieve this in mice. Therefore, I knew we needed a more realistic strategy.

“We could replace the diseased astrocytes in patients with fresh, healthy ones. This approach could improve the environment surrounding existing motor neurons.”

Svendsen combined two strategies: replacing astrocytes and delivering GDNF.

He and his team planned to create healthy astrocytes from human neural stem cells. These cells would also produce therapeutic levels of GDNF.

They would then transplant the cells into patients’ spinal cords.

Patients cannot take GDNF as a pill because the growth factor cannot reach the brain or spinal cord.

Instead, the transplanted astrocytes would release GDNF near the motor neurons. The factor could then help keep those neurons healthy and alive.

With critical funding from a CIRM Disease Team grant, Svendsen and his Cedars-Sinai colleagues tested this approach in rats with ALS.

They transplanted human neural stem cells, also called neural progenitor cells, into the rats.

The cells successfully developed into astrocytes and released GDNF. Together, these effects protected the rats’ motor neurons.

Svendsen describes the strategy as “a double whammy.” It combines healthy astrocyte replacement with GDNF delivery to protect motor neurons.

“Replacing astrocytes could rejuvenate the environment surrounding motor neurons,” he said. “I think this approach offers a powerful experimental strategy for treating ALS.”

A fifteen year journey from bench to bedside

With promising preclinical data under his belt, Svendsen and his colleagues, including Robert Baloh, MD, PhD, director of neuromuscular medicine at the Cedars-Sinai Department of Neurology, and neurosurgeon J. Patrick Johnson, MD, designed a clinical trial that would test this experimental therapy in ALS patients. In October 2016, CIRM approved funding for a Phase I/IIa clinical trial assessing the safety of this novel human neural progenitor cell and gene therapy.

This is a first-in-human study, and as such, the U.S. Food and Drug Administration (FDA) required the team to transplant the cells into only one side of the lumbar spinal cord, which effectively means that only one of the patient’s legs will get the treatment. This will allow for a comparison of the function and progression of ALS in the leg on the treated side of the spinal cord compared with the leg on the untreated side.

The trial was approved to treat a total of 18 patients and started in May 2017.

 Svendsen, who first started working on ALS back in 2002, describes his path to the clinic as a “very long and windy road.” He emphasized that this journey wouldn’t be possible without the hard work of his team, Cedars-Sinai and financial support from CIRM.

“It took ten years of preclinical studies and an enormous amount of work from many different people. Just producing the cells that we’re going to use took three years and a lot of trials and tribulations to make it a clinically viable product. It was really thanks to CIRM’s funding and the support of Cedars-Sinai that we got through it all. Without that kind of infrastructure, I can safely say we wouldn’t be here today.”

This “behind-the-scenes” view of how much time and effort it takes to translate a stem cell therapy from basic research into the clinic isn’t something that the public is often exposed to or aware of. Just as “Rome wasn’t built in a day,” Svendsen stressed that good quality stem cell trials take time, and that it’s important for people know how complicated these trials are.

It’s all about the patients

So, what motivates Svendsen to continue this long and harrowing journey to develop a treatment for ALS? He said the answer is easy. “I’m doing it for the patients,” he explained. “I’m not doing this for the money or glory. I just want to develop something that works for ALS, so we can help these patients.”

Svendsen revisited his story about Jeff Kaufman, a man he befriended at the Wisconsin ALS Chapter in 2003. Jeff had three daughters and a son, a wonderful wife, and was a successful lawyer when he was diagnosed with ALS.

“Jeff had basically everything, and then he was stricken with ALS. I still remember going to his house and he could only move his eyes at that point. He tapped out the words ‘Can stem cells help me Clive?’ on his computer screen. And my heart sank because I knew how much and how long it was going to take. I was very realistic so I said, ‘Yes Jeff, but it’s going to take time and money. And even then, it’s a long shot.’ And he told me to go for it, and that stuck in my brain.”

It’s people like Jeff that make Svendsen get out of bed every morning and doggedly pursue a treatment for ALS. Sadly, Jeff passed away due to complications from ALS in 2010. Svendsen says what Jeff and other patients go through is tragic and unfair.

“There’s a gene that goes along with ALS and it’s called the ‘nice person gene,’” he said. “People with ALS are nice. I can’t explain it, but neurologists would say the same thing. You feel like it’s just not fair that it happens to those people.”

The future of stem cell therapies for ALS

It’s clear from speaking with Svendsen, that he is optimistic about the future of stem cell-based therapies for ALS. Scientists still need to unravel the actual causes of ALS. But the experimental stem cell treatments currently in development, including Svendsen’s, will hopefully prove effective at delaying disease progression and give ALS patients more quality years to live.

In the meantime, what concerns Svendsen is how vulnerable ALS patients are to being misled by unapproved stem cell clinics that claim to have cures. “Unfortunately, there are a lot of charlatans out there, and there are a lot of false claims being made. People feed off the desperation that you have in ALS. It’s not fair, and it’s completely wrong. They’ll mislead patients by saying ‘For $40,000 you can get a cure!’”

Compelling stories of patients cured of knee pain or diseases like ALS with injections of their own adult stem cells pop up in the news daily. Many of these stories refer to unapproved treatments from clinics that don’t provide scientific evidence that they’re safe and effective. Svendsen said reasonable, research-backed trials are attempting to use adult stem cells to treat ALS. He commented, “I think it’s hard for the public to wade through all of these options and understand what’s real and what’s not real.”

Svendsen’s advice for ALS patients interested in enrolling in a stem cell trial or trying a new stem cell treatment is to be cautious. If a therapy sounds too good to be true, it probably is, and if it costs a lot of money, it probably isn’t legitimate, he explained.

He also wants patients to understand the reality of the current state of ALS stem cell trials. The approved stem cell trials he is aware of are not at the treatment stage yet.

“If you’re enrolled in a stem cell trial that is funded and reputable, then they will tell you honestly that it’s not a treatment. There is currently no approved treatment using stem cells for ALS,” Svendsen said.

This might seem like discouraging news to patients who don’t have time to wait for these trials to develop into treatments, but Svendsen pointed out that when he started his research 15 years ago, the field of stem cell research was still in its infancy. A lot has been accomplished in the past decade-and-a-half, and with talented scientists dedicated to ALS research like Svendsen, the next 15 years will likely offer new insights into ALS and hopefully stem cell-based treatments for a devastating disease that has no cure.

Svendsen hopes that one day, when someone like Jeff Kaufman asks him, “Can stem cells help me, Clive?” He’ll be able to say, yes they can, yes they can.