Experimental drug shields nerve cells from damage caused by ALS

Amyotrophic Lateral Sclerosis, or ALS, received widespread awareness in the summer of 2014 thanks to an Ice Bucket Challenge. Millions of people participated in the challenge, drenching themselves in ice cold water to bring visibility to this devastating neurodegenerative disease and generate charitable donations for research.

The challenge takes place every year, but ALS still has no known treatment or cure. 

Now, University of Arizona researchers have found a promising experimental drug that could shield nerve cells from the damage of ALS. Working in mice and in human nerve cells in the brain and spinal cord, the researchers found that blocking a small part of a key protein involved in ALS protects the nerve cells that the disease damages. 

"Current FDA-approved treatments for ALS provide only modest benefits. There is an urgent need for a real breakthrough," said Xinglong Wang, senior author of the study published in Nature Aging and a professor at the R. Ken Coit College of Pharmacy.

Wang published the study along with first author Dr. Ju Gao, an assistant research professor at the Coit College of Pharmacy.

ALS is difficult to treat because it is often diagnosed only after substantial nerve cell damage has already occurred. The first sign is often weakness in a leg or an arm, Wang said, but by the time the symptoms show up, much of the damage is already done. 

For most patients, the cause of ALS is a mystery. Fewer than one in 10 cases are inherited through a known genetic mutation. The rest, more than 90%, arise sporadically with no family history and no clear genetic cause. However, nearly all cases share one thing in common. A protein called TDP-43 clumps abnormally inside nerve cells, whether the disease is inherited or not. That clumping is now the commonly used to confirm the diagnosis at autopsy.

TDP-43 is not a foreign or a defective protein, but a protein that nearly all cells normally make and need to function. In ALS, TDP-43, which usually resides in brain's nerve cells, drifts out of the cells and forms toxic clumps. Several theories point to many possible drug targets to clear the clumps, but none have led to an effective treatment. Wang's team took a different approach by looking directly at the protein itself. 

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?"

Xinglong Wang, senior author of the study

The team found a small region in the protein that was nearly identical across species from mice to humans with many disease-causing mutations clustering there. When they deleted this region in mice, the nerve cell death caused by TDP-43 dropped sharply. Removing it also left the protein's normal function intact. Wang said the work took a decade with much of it spent to confirm that the deletion did not disturb healthy function and cause any side effects. 

After rigorous testing, Wang's team narrowed down on an experimental drug, XL20, which could latch onto the target region in the TDP-43 protein. Most importantly, the drug could cross the blood-brain barrier, the filter that keeps most drugs out of the brain. 

In mice, the experimental drug extended median survival by about a week, a meaningful gain against the short life span of mice. XL20 also protected the nerve cells and reduced muscle weakness. Also, in the lab, the team tested XL20 on human motor neurons, the specialized nerve cells in the brain and spinal cord, where it reversed some of the same damage. 

Because XL20 targets TDP-43 directly and already works in human nerve cells, Wang said it represents a promising candidate for future clinical development. Also, since ALS typically develops over months to years after symptoms first appear, Wang said earlier treatment could offer a greater opportunity to slow disease progression. 

The study's findings may reach well beyond ALS, Wang said. The same TDP-43 pathology or abnormality is central to a common age-related dementia called LATE, or limbic-predominant age-related TDP-43 encephalopathy, which affects roughly one in three people over 80. TDP-43 pathology is also found in more than half of Alzheimer's patients and is associated with faster cognitive decline.

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