Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis

Genetic FTD Initiative (GENFI), Katherine M. Wilson, Eszter Katona, Idoia Glaria, Mireia Carcolé, Imogen J. Swift, Aitana Sogorb-Esteve, Carolin Heller, Arabella Bouzigues, Amanda J. Heslegrave, Ashvini Keshavan, Kathryn Knowles, Saurabh Patil, Susovan Mohapatra, Yuanjing Liu, Jaya Goyal, Raquel Sanchez-Valle, Robert Jr Laforce, Matthis Synofzik, James B. RoweElizabeth Finger, Rik Vandenberghe, Christopher R. Butler, Alexander Gerhard, John C. Van Swieten, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Alexandre De Mendonça, Mario Masellis, M. Carmela Tartaglia, Markus Otto, Caroline Graff, Simon Ducharme, Jonathan M. Schott, Andrea Malaspina, Henrik Zetterberg, Ramakrishna Boyanapalli, Jonathan D. Rohrer, Adrian M. Isaacs

Research output: Contribution to journalArticlepeer-review


Objective: A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay. Methods: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS. Results and conclusions: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts.

Original languageEnglish
Pages (from-to)761-771
JournalJournal of Neurology, Neurosurgery and Psychiatry
Issue number7
Publication statusPublished - 2022



ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health


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