Related Experiment Video
Updated: Sep 10, 2025
Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System
Published on: May 12, 2013
Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS
Zachary T McEachin1, Mingee Chung2, Sabrina A Stratton2
1Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA.
Abstract:
C9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic G4C2 repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.
Insights
Antisense oligonucleotide BIIB078 for C9orf72-associated ALS showed widespread distribution but failed to impact key CNS pathologies. Further research is needed for effective pharmacodynamic biomarkers in ASO therapies.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- C9orf72-associated ALS stems from G4C2 repeat expansions, producing toxic RNA and dipeptide repeat proteins (DPRs).
- A clinical trial with BIIB078, an antisense oligonucleotide (ASO) targeting these transcripts, was discontinued due to lack of clinical benefit.
Purpose of the Study:
- To assess BIIB078's central nervous system (CNS) target engagement.
- To identify pharmacodynamic cerebrospinal fluid (CSF) biomarkers post-treatment.
Main Methods:
- Analysis of CSF and postmortem CNS tissue from BIIB078-treated patients.
- Quantification of DPRs, phosphorylated TDP-43, and proteomic signatures.
- Measurement of inflammatory biomarkers and RNase T2 abundance.
Main Results:
- Reduced DPRs and increased inflammatory biomarkers (CCL26) in CSF.
- Widespread BIIB078 distribution in CNS tissue, but persistent DPRs and pTDP-43.
- No significant alteration in spinal cord proteomic signatures, except for RNase T2 increase correlated with BIIB078 levels.
Conclusions:
- BIIB078 demonstrated limited impact on core CNS pathologies in c9ALS despite distribution.
- The study highlights the critical need for pharmacodynamic biomarkers reflecting neuropathological changes for ASO efficacy assessment.
Related Concept Videos
02:30siRNA - Small Interfering RNAs
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the...
02:15Experimental RNAi
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...