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Publication
Cell

Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS

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  • August 26, 2025
  • Johnathan D. Glass, Emory University
Topic/Product:
CNS Disease Panel 120, Inflammation Panel 250, Neurology
Disease Area:
ALS
Sample Type:
CSF

Summary

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.

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Authors & Affiliations

Zachary T. McEachin,1,2,3,4,12,*; Mingee Chung,1,2,3; Sabrina A. tratton,1,2,3; Changhee Han,1,3; Woo Jae Kim,1,3; Udit Sheth,5,6; Eleanor V. Thomas,4,7; Ethan Issenberg,1,3; Tanvi Kamra,1,3; Paola Merino,4,8; Yona Levites,4,8; Nisha Raj,1,2,3;  Eric B. Dammer,4,9; Duc M. Duong,4,9; Lingyan Ping,4,9; Anantharaman Shantaraman,4,9; Adam N. Trautwig,4,9;  Joshna Gadhavi,4,9; EzanaAssefa,4,7; Marla Gearing,4,7,10; Kaylor M. Kelly,4,10; Shanu F. Roemer,6; Michael DeTure,6;  Seneshaw Asress,4,7; Thomas Kukar,4,7,8; Christina Fournier,7; Dennis W. Dickson,5,6; Leonard Petrucelli,5,6 Todd E. Golde,4,7,8; Bjorn Oskarsson,11; Tania F. Gendron,5,6; Nicholas T. Seyfried,4,7,9,*; and Jonathan D. Glass 4,7,10,*

1Department of Human Genetics, Emory University, Atlanta, GA 30322, USA 2Department of Cell Biology, Emory University, Atlanta, GA 30322, USA 3Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA 4Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA 5Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic, Jacksonville, FL 32224, USA 6Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA 7Department of Neurology, Emory University, Atlanta, GA 30322, USA 8Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA 9Department of Biochemistry, Emory University, Atlanta, GA 30322, USA 10Department of Pathology, Emory University, Atlanta, GA 30322, USA 11Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.