University of Arizona researchers announced on July 3 that an experimental drug may protect nerve cells from the damage caused by Amyotrophic Lateral Sclerosis, or ALS. The study, published in Nature Aging, found that blocking a small part of a key protein involved in ALS protected nerve cells in both mice and human brain and spinal cord samples.
Xinglong Wang, senior author of the study and professor at the R. Ken Coit College of Pharmacy, said, "Current FDA-approved treatments for ALS provide only modest benefits. There is an urgent need for a real breakthrough." Wang collaborated with first author Dr. Ju Gao, an assistant research professor at the Coit College of Pharmacy.
ALS remains difficult to treat because it is often diagnosed after significant nerve cell damage has already occurred. While fewer than one in ten cases are inherited through known genetic mutations, over 90% arise sporadically without clear genetic causes. Nearly all cases share abnormal clumping of a protein called TDP-43 inside nerve cells; this clumping is now commonly used to confirm diagnosis at autopsy.
The research team identified a small region within TDP-43 that was nearly identical across species and where many disease-causing mutations cluster. Deleting this region in mice sharply reduced nerve cell death without affecting normal protein function. After extensive testing over a decade to ensure no side effects or loss of healthy function, the team focused on an experimental drug named XL20, which targets this region and can cross the blood-brain barrier.
In mouse models, XL20 extended median survival by about a week—considered meaningful given their short lifespan—and protected nerve cells while reducing muscle weakness. In laboratory tests on human motor neurons from brain and spinal cord tissue, XL20 reversed some damage seen with ALS pathology.
Wang said XL20 represents a promising candidate for future clinical development due to its direct targeting of TDP-43 and effectiveness in human cells: "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."
