An international team of biologists has found a way to slow amyotrophic lateral sclerosis – a fatal neurodegenerative disease that afflicted the late British astrophysicist Stephen Hawking – using an experimental drug called XL20 that neutralises toxic clumps of the TDP‑43 protein.
“Existing approved drugs only slightly alleviate patients’ condition. We asked ourselves a simple question that no one had tried to answer before – is there a specific part of the TDP‑43 protein that kills neurons, and can we suppress the disease by blocking it without disrupting the protein’s normal function,” said Wang Xinglun, a professor at the University of Arizona.
Previous attempts to develop drugs that break down TDP‑43 aggregates have failed in trials.
In developing the new drug, the researchers compared the structures of different TDP‑43 forms found in brain cells from healthy individuals, ALS patients, mice and several other animals. This allowed them to identify a small region in the protein’s so‑called C‑terminal that plays a key role in clump formation but whose removal does not disable TDP‑43.
The team then created a short molecule, XL20, that blocks this region of TDP‑43 and prevents it from forming clumps. The drug has already been tested in mice with ALS and showed a positive effect.