2. Academic Validation
  3. Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS

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

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: zmceach@emory.edu.
  • 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: nseyfri@emory.edu.
  • 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: jglas03@emory.edu.
PMID: 40865525 DOI: 10.1016/j.cell.2025.07.045
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.

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