Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS PMID: 40865525

ADC Targets in Oncology

2026-04-10

Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS

Cell. 2025 Aug 26:S0092-8674(25)00908-0. doi: 10.1016/j.cell.2025.07.045.

Zachary T McEachin ¹ , Mingee Chung ² , Sabrina A Stratton ² , Changhee Han ³ , Woo Jae Kim ³ , Udit Sheth ⁴ , Eleanor V Thomas ⁵ , Ethan Issenberg ³ , Tanvi Kamra ³ , Paola Merino ⁶ , Yona Levites ⁶ , Nisha Raj ² , Eric B Dammer ⁷ , Duc M Duong ⁷ , Lingyan Ping ⁷ , Anantharaman Shantaraman ⁷ , Adam N Trautwig ⁷ , Joshna Gadhavi ⁷ , Ezana Assefa ⁵ , Marla Gearing ⁸ , Kaylor M Kelly ⁹ , Shanu F Roemer ¹⁰ , Michael DeTure ¹⁰ , Seneshaw Asress ⁵ , Thomas Kukar ¹¹ , Christina Fournier ¹² , Dennis W Dickson ⁴ , Leonard Petrucelli ⁴ , Todd E Golde ¹¹ , Björn Oskarsson ¹³ , Tania F Gendron ⁴ , Nicholas T Seyfried ¹⁴ , Jonathan D Glass ¹⁵

Affiliations

1. Department 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. Electronic address: [email protected].
2. Department 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.
3. Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
4. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
5. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA.
6. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
7. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
8. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pathology, Emory University, Atlanta, GA 30322, USA.
9. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Pathology, Emory University, Atlanta, GA 30322, USA.
10. Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
11. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
12. Department of Neurology, Emory University, Atlanta, GA 30322, USA.
13. Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
14. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Biochemistry, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected].
15. Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pathology, Emory University, Atlanta, GA 30322, USA. Electronic address: [email protected].

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.

Keywords

BIIB078; C9orf72; NULISA; TDP-43; amyotrophic lateral sclerosis; antisense oligonucleotides; dipeptide repeat proteins; proteomics.