XL20 drug candidate shields motor neurons from ALS-linked TDP-43 damage

Researchers at the University of Arizona have identified a promising experimental drug that could help protect nerve cells from the damage caused by amyotrophic lateral sclerosis (ALS).

The drug, known as XL20, protected nerve cells in both mice and human motor neurons by targeting a specific region of a protein strongly linked to ALS and could offer a potential new approach to treating the neurological condition.

ALS, also known as motor neurone disease, progressively destroys the nerve cells responsible for controlling voluntary muscle movement and is often diagnosed after significant and irreversible damage has already occurred, limiting the effectiveness of current treatments.

Targeting a key protein

The exact cause of ALS remains unknown in most patients. Fewer than one in 10 cases are inherited, while the vast majority develop without any clear genetic cause.

Despite these differences, almost all ALS cases share a common feature: the abnormal accumulation of a protein called TDP-43 inside nerve cells. Normally essential for healthy cell function, TDP-43 forms toxic clumps in the brains and spinal cords of people with ALS and is commonly used to confirm the diagnosis after death.

Previous research has focused on removing these protein clumps, but without producing an effective treatment. Instead, the Arizona team investigated whether one specific section of the protein was responsible for causing the damage.

Almost all ALS cases share a common feature: the abnormal accumulation of a protein called TDP-43 inside nerve cells

“We asked a simple question that had never been tested: is there one specific part of TDP-43 that’s causing the harm, something a drug could switch off without disturbing the rest?” said Xinglong Wang, a senior author of the study and Professor at the R. Ken Coit College of Pharmacy.

The researchers identified a small region of TDP-43 that is almost identical across multiple species and contains many disease-causing mutations. Removing this section in mice dramatically reduced nerve cell death while leaving the protein’s normal functions intact.

According to Wang, the work took around a decade, with much of that time spent confirming that removing the targeted region did not disrupt healthy cell activity or produce unwanted side effects.

Promising laboratory results

The team subsequently identified XL20 as a compound capable of binding to the targeted region of TDP-43. Crucially, the drug was able to cross the blood-brain barrier, a major obstacle that prevents many medicines from reaching the brain.

In mouse studies, treatment with XL20 extended median survival by around one week, reduced muscle weakness and protected nerve cells from degeneration.

The team subsequently identified XL20 as a compound capable of binding to the targeted region of TDP-43

Researchers also tested the drug on human motor neurons grown in the laboratory, where it reversed some of the same cellular damage associated with ALS.

Because XL20 acts directly on TDP-43 and has already shown activity in human nerve cells, the researchers believe it represents a promising candidate for future clinical development. They also suggest that earlier treatment following diagnosis could provide greater opportunities to slow disease progression.

Potential beyond ALS

The findings could have implications for other neurodegenerative disorders in which TDP-43 abnormalities play a significant role.

“The same TDP-43 pathology is implicated in several other neurodegenerative diseases,” said Wang. “If future studies show this approach works in those diseases as well, it could eventually benefit a much larger patient population.”

The same TDP-43 pathology is implicated in several other neurodegenerative diseases

TDP-43 abnormalities are also associated with limbic-predominant age-related TDP-43 encephalopathy (LATE), a common form of dementia affecting older adults and are found in more than half of people with Alzheimer’s disease, where they have been linked to faster cognitive decline.

While XL20 remains an experimental treatment and further studies will be required before it can be tested in patients, the research offers a potential new strategy for tackling ALS by targeting one of the disease’s defining biological features.