Overcoming Protein Buildup and Patient Heterogeneity: The Dual Challenge for ASO Therapies

A new Emory University study reveals why a once-promising experimental amyotrophic lateral sclerosis (ALS) drug, despite successfully reaching its intended target in the central nervous system (CNS)—the brain and spinal cord—failed to help patients.

The therapy, called BIIB078, is an antisense oligonucleotide (ASO), a short strand of synthetic genetic material designed to block the production of toxic RNA and proteins in patients with inherited ALS linked to the C9orf72 gene. This gene mutation is the most common genetic cause of the disease. A clinical trial of BIIB078 was halted in 2021 after patients showed no clinical improvement.

"Disease-specific biomarkers in cerebrospinal fluid (CSF) indicated that the ASO hit its intended target, but it was unclear whether it penetrated CNS tissue and affected the disease itself," said Zachary McEachin, PhD, assistant professor of human genetics and co-senior author of the study. "Getting a drug to the CNS is only part of the challenge. We need better methods to understand whether a treatment actually changes the course of ALS. Our study addresses some of these questions and shows that CSF biomarkers do not always reflect changes in the CNS."

In this new analysis of samples from trial participants, researchers examined CSF samples collected during life, as well as brain and spinal cord tissue collected postmortem. The study included eight patients with C9orf72-related ALS (c9ALS) who received BIIB078 and 31 ALS patients who did not receive the drug. They found that the drug was widely distributed throughout the central nervous system and reduced some toxic proteins associated with ALS. However, it did not improve or reverse key disease processes that drive ALS, such as the accumulation of abnormal brain proteins.

"This study is an important step toward better understanding the biological effects of ASO therapies in patients with neurological diseases," says co-senior author Jonathan Glass, M.D., professor in the Department of Neurology at Emory University School of Medicine. "Several ASO therapies are currently in clinical use or trials. We expect our new data will have an impact on the development of new ASO-directed therapies."

Figure 1. Intrathecally delivered BIIB078 ASO results in broad and sustained CNS penetration. (McEachin Z T, et al., 2025)

Researchers noted that patient variability in biological responses to ASO treatment highlights the need to understand how individuals respond to therapeutic interventions, a crucial question for achieving the goals of precision and personalized medicine. The ALS Center researchers are members of the Center for Neurodegenerative Diseases at the Goizueta Brain Health Institute.

"This study, utilizing an integrated proteomic approach to rigorously assess molecular changes in tissue and CSF following ASO treatment, provides new therapeutic biomarkers and insights for better design and monitoring of future clinical trials," said co-senior author Nicholas Seyfried, PhD, professor of biochemistry.

ALS, also known as Lou Gehrig's disease, is a progressive disease that attacks the nerve cells that control muscle movement. Most ALS patients survive only two to five years after diagnosis, and effective treatments remain limited. While the majority of ALS cases are sporadic, this study specifically focused on the less common inherited forms, which account for approximately 10% of all cases.

These findings highlight the urgent need for new tools—biomarkers—that can show in real time whether experimental therapies are having a meaningful impact on the disease.

Reference

McEachin Z T, et al. Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS. Cell, 2025.