A recent study from Emory University has provided new insights into why a promising experimental drug for amyotrophic lateral sclerosis (ALS) did not lead to clinical improvement in patients, despite reaching its intended target in the central nervous system.
The research was conducted by the Emory ALS Center and the Center for Neurodegenerative Disease at Emory’s Goizueta Brain Health Institute. The therapy studied, BIIB078, is an antisense oligonucleotide (ASO) designed to block toxic RNA and proteins in people with a genetic form of ALS linked to mutations in the C9orf72 gene. This mutation is known as the most common inherited cause of ALS. A clinical trial of BIIB078 ended in 2021 after it failed to show benefits for patients.
“Disease-specific biomarkers in the cerebrospinal fluid (CSF) suggested that the ASO was hitting its intended target, but it was not clear if it penetrated CNS tissue and affected the disease itself,” said Zachary McEachin, PhD, assistant professor of Human Genetics and lead and co-senior author. “Getting the drug to the CNS is only part of the challenge. We need better ways to know whether a treatment is truly changing the course of ALS. Our study addresses some of those questions and shows that CSF biomarkers do not always reflect changes in the CNS.”
Researchers analyzed samples from eight individuals with C9orf72-linked ALS who received BIIB078 and compared them with 31 ALS patients who did not receive the drug. They examined both CSF collected during life and postmortem brain and spinal cord tissue.
Findings showed that while BIIB078 spread throughout the central nervous system and reduced some toxic proteins associated with ALS, it did not improve or reverse key disease processes such as abnormal protein buildup in brain cells.
“This work is an important step forward to better understanding the biology of ASO therapies in people with neurological diseases,” said Jonathan Glass, MD, director of the Emory ALS Center and professor in neurology at Emory University School of Medicine. “Several ASO therapies are either now in clinical use or in trial. We expect our new data will be influential in the development of new ASO-directed therapies.”
The study also noted differences among patients’ biological responses to treatment, underlining a need for more personalized approaches when developing future therapies.
“This work utilized integrated proteomic approaches to rigorously evaluate molecular changes in both tissue and CSF following ASO therapy, providing new biomarkers of treatment and insights to better design and monitor future clinical trials,” said Nicholas Seyfried, PhD, professor of Biochemistry and co-senior author.
ALS affects nerve cells responsible for muscle movement; most patients survive two to five years after diagnosis. While most cases are sporadic rather than inherited, this research focused on genetic forms accounting for about 10% of all cases.
The results highlight a pressing need for improved biomarkers that can indicate whether experimental treatments are having meaningful effects on disease progression.
