Breakthrough study reveals potential treatment path for ALS

Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig's disease, is an incurable neurological disorder affecting motor neurons-nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing.

Many ALS clinical trials, including those testing promising drugs, have fallen short of expectations-often because the extent of the disease can vary, and patients don't respond the same way to medications.

But a new study led by scientists at Case Western Reserve University used stem cells created from ALS patients to target a specific gene as a kind of shut-off valve for what stresses nerve cells -and it worked.

Although the research involved a very rare type of ALS, the research team was optimistic the positive results could provide clues for potentially treating the devastating disorder more broadly.

This work could help lay the foundation for genetically informed clinical trials."

Helen Cristina Miranda, lead researcher, associate professor of genetics and genome sciences at Case Western Reserve's School of Medicine

Regenerative medicine-generating healthy cells to replace cells and repair tissues damaged by disease-is a particular strength at Case Western Reserve. Miranda's lab studies neurodegenerative diseases-including ALS-using human stem cells.

The study was published today in the peer-reviewed journal EMBO Molecular Medicine.

The study

The researchers studied an inherited type of ALS caused by a mutation in a gene (vesicle-associated membrane protein B, or VAPB). The VAPB gene provides instructions for making a protein that helps link different parts of the cell so they can communicate and respond to stress.

"This is especially important in nerve cells," Miranda said. "When they break down, the neurons become more vulnerable to degeneration."

iPSC, or induced pluripotent stem cell, are special cells created in the lab from a person's skin or blood that can be turned into almost any cell type in the body. In this study, they used iPSCs from ALS patients to grow their motor neurons in a dish, allowing them to study the disease using real human cells.

• They discovered how a mutation in the VAPB gene can disrupt communication between key parts of the cell, specifically between the endoplasmic reticulum (ER) and mitochondria. The ER is like the cell's quality control center. It helps produce and fold proteins and makes sure everything inside the cell is running smoothly, especially when the cell is under stress. Mitochondria are the cell's power plants. They generate the energy that cells-especially nerve cells-need to stay alive and do their jobs.

• This disruption leads to chronic activation of a protective mechanism called the

Integrated Stress Response (ISR). Although initially helpful, sustained ISR

activation reduces protein production and impairs cell survival, ultimately

damaging motor neurons and contributing to this rare inherited form of ALS.

• They also identified the ISR as a potential therapeutic target.

"We also showed that blocking this stress response can reverse damage in the lab, a promising step toward future treatments," she said. "That's a promising proof-of-concept for future therapeutic strategies."

What's next

Several medications approved for ALS by the U.S. Food and Drug Administration may prolong survival, slow the rate of decline or help manage symptoms. But there's no known treatment that stops or reverses the disorder's progression.

As explained, the team's study focused on a particular rare type of ALS. But the hope is to now expand the research to test whether the target might work on other forms of the disorder.

"It's very rare, more prevalent in Brazil, but studying it gives us a window into how ALS motor neurons respond to stress," Miranda said. "We are now testing ISR inhibitors in more complex neuromuscular models and exploring how this approach might benefit other ALS subtypes."