CAR T-cell therapy can slow neurodegenerative conditions such as ALS

Genetically engineered immune cells known as CAR-T cells may be able to slow the progression of the neurodegenerative condition amyotrophic lateral sclerosis (ALS) by killing rogue immune cells in the brain.

“There is no one way to cure the disease,” says Davide Trotti of the Jefferson Weinberg ALS Center in Pennsylvania. “The goal is to slow down the disease.”

Life expectancy for people diagnosed with ALS is only two to five years, so slowing the condition’s progression will make a big difference, says Trotti. It is possible that the same approach could also help slow down other neurodegenerative conditions.

Also known as Lou Gehrig’s disease, ALS is caused by the loss of motor neurons, the nerve cells that control voluntary muscles. Physicist Stephen Hawking had ALS, but his case was exceptional because he lived so long. Fewer than 10 percent of people diagnosed with the condition survive more than a decade.

There has been some progress in developing treatments for forms of ALS caused by genetic mutations, says Trotti, but these make up only 5 to 10 percent of cases. For the sporadic forms of ALS whose causes are unknown, there are no treatments.

However, there is evidence that inflammation in the brain contributes to the death of motor neurons. In particular, some of the immune cells known as microglia appear to go into an overactive state.

Microglia normally defend the brain against infection, clean up debris and help prune redundant connections, or synapses, between neurons. But if some of them become overactive, they can remove too many synapses and contribute to the loss of neurons. “They get out of control,” says Trotti.

In a series of experiments that included studies of brain and spinal cord tissue from people with ALS, Trotti’s team has shown that these damage-amplifying microglia, as they are known, have a lot of a protein called uPAR sticking out of their surface. “So they’re tagged, and once we know the tag, we can go after them and remove them from the central nervous system,” says Trotti.

To do this, the team turned to CAR-T cells, immune cells that are genetically engineered to kill cells with specific proteins on their surface. CAR-T cells have been shown to be highly effective in treating certain types of cancer, and are now being tested to treat a much wider range of conditions, such as the autoimmune condition lupus.

In studies of cells growing in culture, the team has shown that CAR-T cells targeting uPAR can kill rogue microglia without harming neurons. So while this treatment cannot replace lost motor neurons, the hope is that it will slow further loss.

Trials are now underway on mice with a mutation that causes them to develop a form of ALS, with results expected within a year or so. The seriousness of ALS and its lack of treatments means regulators could help speed up human trials if those results are promising.

“The evidence for immune dysfunction in ALS is increasing,” says Ammar Al-Chalabi of King’s College London, whose team has been testing immune-related therapies for ALS. “This seems like a very promising and interesting approach to me.”

It is likely that damage-amplifying microglia also contribute to other neurodegenerative conditions, perhaps including types of dementia, so this treatment may prove to have broader applications beyond ALS. “It might be a way to slow down those kinds of neurodegenerative conditions,” says Trotti.

CAR-T cells have some major drawbacks as a therapy: they can trigger serious side effects, and because they are usually derived from a person’s own cells, they are very expensive to produce. But many teams around the world are working on ways to make them safer and cheaper, for example by generating them inside the body so that cells don’t have to be extracted.