PXD055796-1

PXD055796 is an original dataset announced via ProteomeXchange.

Title	Spinal Cord Proteomics of Antisense Oligonucleotide Drug Trial
Description	C9orf72-linked amyotrophic lateral sclerosis (c9ALS) is driven by an intronic G4C2 repeat expansion, leading to the production of 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 meet secondary efficacy endpoints, despite a reduction in DPRs in cerebrospinal fluid (CSF). The extent of target engagement in the central nervous system (CNS) and the relevance of pharmacodynamic CSF biomarkers following BIIB078 treatment remain unclear. Post-mortem analysis of CNS tissue from six BIIB078-treated c9ALS patients revealed widespread intracellular BIIB078 distribution in the spinal cord and brain regions, persisting for over a year after the last dose. C9orf72 mRNA levels were inversely correlated with BIIB078 concentration, indicating partial target engagement. Despite reductions in CSF DPRs, these proteins and phosphorylated TDP-43 remained abundant in the brain and spinal cord, suggesting that CSF biomarkers may not fully reflect CNS target engagement. Additionally, sustained increases in inflammation biomarkers, including CCL26, GDF15, and other cytokines, were observed. Global proteomic analysis of spinal cord tissue revealed significant changes in c9ALS cases that were not normalized in BIIIB078 treated cases. Notably, proteome-wide correlations with BIIB078 concentration in the spinal cord identified hydrolytic nucleases, including RNASET2 and DNASE2, to be increased in BIIB078 treated cases. Thus, while BIIB078 demonstrated widespread and sustained distribution and partial target engagement, it did not significantly impact key proteomic and pathological features in the CNS of c9ALS patients. Consequently, ceasing strategies that target the G4C2 sense strand may be premature.
HostingRepository	PRIDE
AnnounceDate	2025-08-27
AnnouncementXML	Submission_2025-08-27_11:37:17.791.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Dammer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-11 20:22:14	ID requested
⏵ 1	2025-08-27 11:37:18	announced

10.1016/J.CELL.2025.07.045;

submitter keyword: C9Orf72, ASO,Human Spinal Cord, ALO

Zachary McEachin
contact affiliation	Assistant Professor Emory University School of Medicine, Department of Human Genetics
contact email	zmceach@emory.edu
lab head
Eric Dammer
contact affiliation	Emory University
contact email	edammer@emory.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD055796

PRIDE project URI

• PRIDE
  1. PXD055796
     1. Label: PRIDE project
     2. Name: Spinal Cord Proteomics of Antisense Oligonucleotide Drug Trial