CAR-T cells, a revolutionary form of immunotherapy, have the potential to slow the progression of amyotrophic lateral sclerosis (ALS) by eliminating dysfunctional immune cells in the brain.

“That’s not how to cure a disease,” notes Davide Trotti from the Jefferson Weinberg ALS Center in Pennsylvania. “The goal is to slow the disease’s progression.”

Individuals diagnosed with ALS typically have a life expectancy of only two to five years. Thus, any method to slow the disease’s advancement could significantly improve patient outcomes, Trotti said. This approach may also benefit the treatment of other neurodegenerative disorders.

ALS, or Lou Gehrig’s disease, results from the degeneration of motor neurons, the nerve cells responsible for voluntary muscle control. Physicist Stephen Hawking’s case was noteworthy, as he lived far longer than most individuals diagnosed with this condition. Fewer than 10 percent of ALS patients survive beyond a decade.

According to Trotti, strides have been made in ALS treatment development, focusing primarily on genetic mutations that constitute 5 to 10 percent of cases. However, there remains no cure for the sporadic type of ALS, whose etiology is largely unknown.

Research indicates that inflammation in the brain contributes to motor neuron death. Specifically, an overabundance of certain immune cells, called microglia, has been observed.

Microglia typically serve as protectors of the brain against infections, help clear debris, and prune unnecessary synapses. However, when overly activated, they can lead to the loss of neurons. “They go overboard,” Trotti explains.

In their studies, Trotti’s team analyzed brain and spinal cord samples from ALS patients, discovering that activated microglia exhibit high levels of a protein known as uPAR. “This protein acts as a marker, enabling us to trace and eliminate them from the central nervous system,” Trotti added.

His research group utilized CAR-T cells, engineered immune cells designed to target and destroy cells displaying specific proteins on their surfaces. CAR-T cells have shown remarkable success in treating certain cancers and are being tested for a broader spectrum of diseases, including autoimmune disorders like lupus.

In laboratory cell studies, the team found that CAR-T cells targeting uPAR effectively killed rogue microglia without harming healthy neurons. Although this therapy cannot restore lost motor neurons, it holds promise in significantly reducing further neuron loss.

Clinical trials are currently underway using mice with a mutation linked to a specific type of ALS. Results are anticipated in the coming year; the severity of ALS and the lack of effective treatments could prompt regulators to fast-track human trials should the findings be positive.

“Evidence of immune dysfunction in ALS is mounting,” states Ammar Al Chalabi from King’s College London, who is exploring immune-targeted therapies for ALS. “This represents a very promising approach.”

Moreover, microglia that exacerbate damage may play a role in other neurodegenerative diseases, potentially including certain forms of dementia, indicating that this therapy could have wide-ranging applications beyond ALS. “It could be instrumental in slowing down various neurodegenerative conditions,” Trotti remarks.

However, CAR-T therapies carry significant drawbacks, including severe side effects and high manufacturing costs, as they are typically derived from a patient’s cells. Fortunately, research teams worldwide are exploring safer and more cost-effective production methods, such as generating these cells within the body.