Stem cells have enormous potential to treat neurodegenerative disorders like amyotrophic lateral sclerosis (ALS), according to Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine at Cedars-Sinai. Applying stem cell research to ALS has been a passion of his for 20 years, and his team is making meaningful progress.

ALS is a disease that slowly destroys both the upper motor neurons in the brain and the lower motor neurons in the spinal cord. Researchers at Cedars-Sinai are looking for ways to effectively target and protect these cells from dying, and ultimately to prevent loss of muscle control.

“The idea is to use stem cells to model and treat human disease,” said Svendsen. “In our newest trial, we are combining two technologies—stem cell therapy and gene therapy—to target the upper motor neurons. In ALS, the fundamental problem is the loss of upper and lower motor neuron function over the course of years. We want to know how we can stop that from happening.”

Built on Success: Targeting the Lower Motor Neurons

In a previous trial, the Cedars-Sinai research team injected fetal-derived progenitor cells into the spinal cords of ALS patients, targeting the lower motor neurons in that region. The injected cells were engineered to turn into astrocytes—support cells that communicate with and protect the function of motor neurons.

Additionally, the cells were engineered to secrete a protein called glial cell line-derived neurotrophic factor (GDNF), which protects cells and could slow the death of motor neurons.

“We injected the cells into the spinal cord in the hope of affecting lower motor neurons that support leg movement,” said Richard Lewis, MD, director of the Electromyography Lab and a professor of Neurology at Cedars-Sinai. “We learned that the stem cells did remain alive in the spinal cord and secreted GDNF.” This was observed up to 3.5 years after cell delivery.

The team’s primary goals were to establish the safety of the approach and to show that the cells can remain viable and healthy. Having successfully checked both goals off the list, the team still has more work to do to determine the cells’ effect on the motor neurons.

“These patients were quite late in their disease,” said Lewis. “In some patients, the injections didn’t quite get to the region where we wanted them. They were off by a few millimeters. But we do believe there was a small effect in a few patients whose injections were closer to the motor neurons.”

In upcoming trials, the researchers plan to improve injection targeting and study the impact on patients in an earlier stage of the disease, with the hope of seeing effects on the survival of motor neurons and the progression of the disease.

The next logical step was to turn the focus to the upper motor neurons. Since the upper motor neurons initiate movement signals in the brain, protecting them is likely crucial to preserving muscle function in patients with ALS.

“Even if we save the lower motor neurons, if the upper motor neurons that initiate movement die, a person would not be able to activate the lower motor neurons,” said Svendsen.

An Innovative Approach: Targeting the Upper Motor Neurons

This time, the team is putting the GDNF-secreting stem cells into an area of the brain known as the motor cortex, and specifically into the hand-knob region that controls hand movement. This is a unilateral trial design, which means stem cells are injected into one side of the motor cortex while the other side serves as the control.

“We use functional MRI to identify the area of the brain to target,” said Adam Mamelak, MD, director of the Functional Neurosurgery Program and a professor of Neurosurgery at Cedars-Sinai. “We use that information to open the brain exactly over that area, and then we do cortical stimulation mapping by applying electrical current on the surface of the brain and watching the hand move. After that, we do microelectrode recording of individual nerve cells starting on the surface and going down through the layers. All of this helps us pinpoint the exact location for injection.”

Mamelak does a total of 21 injections in two rows across the targeted area, which is about the size of a postage stamp. If the first dose is demonstrated to be safe, a second group of ALS patients will receive a higher dose of cells, with the hope of defining a dose that effectively prevents these nerve cells from dying.

This trial has begun with treatment of the first patient, and patient enrollment is ongoing. The goal is to see if this type of intervention could help patients with some remaining hand function preserve that movement. 

Measuring Progress

The team will compare the treated hand with the control hand to gauge success. Using a computerized model of muscle strength, researchers can quantitatively measure hand strength each month, with more extensive testing every three months. Patients will perform movement and strength tests focused on things like pinching, gripping and pulling pegs from a rack. MRI imaging is also used to monitor arm and hand muscles over time.

“It’s important to remember that this trial is not meant to replace the motor neurons but to protect the remaining neurons the patients have,” said Svendsen.

Patients do need to take immunosuppressants for a few months following the injection, since the fetal-derived cells are from a source not specific to the patient. Safety is paramount in this groundbreaking approach, and researchers want to protect the patients and their quality of life as much as possible.

“If a person with ALS could preserve hand function, that has tremendous value,” said Mamelak. “You could be in a wheelchair, but with hand movement, you can do things like eat and use a computer. There are so many things we depend on our hands to do.” 

The Impact on ALS Treatment

While neither of the trials described will cure ALS right now, they could have a huge impact on the ability to preserve muscle function—and even potentially increase it if diminished—in patients with the disease.

“In the motor cortex, the neurons become sick before dying, and the GDNF released from the astrocytes may make the neurons feel better,” said Svendsen. “Since the cells aren’t dead, it could potentially bring some function back. We just don’t know yet.”

Current approved treatments for ALS only minimally slow the progression of the disease. The Cedars-Sinai research team hopes that this stem-cell injection approach can be applied to stop the progression or prevent it entirely. And this treatment course requires only a single delivery of cells rather than continuously taking medications.

The research team is also developing and optimizing stem cell models of ALS—taking patients’ cells and having them become motor neurons in the culture dish—to better understand disease progression and what causes the motor neurons to die. GDNF appears to have a promising impact.

“If we find GDNF is as effective as we hope it is, there may be delivery systems that will bring the stem cells and GDNF to more regions—including those that affect breathing and swallowing,” said Lewis. “This is a true experiment that will tell us if what we’re doing has a biologic effect on motor neurons and the motor system.”