Katherine M. Wilson, UCL Queen Square Institute of Neurology
Eszter Katona, UCL Queen Square Institute of Neurology
Idoia Glaria, UCL Queen Square Institute of Neurology
Mireia Carcolé, UCL Queen Square Institute of Neurology
Imogen J. Swift, UCL Queen Square Institute of Neurology
Aitana Sogorb-Esteve, UCL Queen Square Institute of Neurology
Carolin Heller, UCL Queen Square Institute of Neurology
Arabella Bouzigues, UCL Queen Square Institute of Neurology
Amanda J. Heslegrave, UCL Queen Square Institute of Neurology
Ashvini Keshavan, UCL Queen Square Institute of Neurology
Kathryn Knowles, UCL Queen Square Institute of Neurology
Saurabh Patil, Wave Life Sciences
Susovan Mohapatra, Wave Life Sciences
Yuanjing Liu, Wave Life Sciences
Jaya Goyal, Wave Life Sciences
Raquel Sanchez-Valle, Universitat de Barcelona
Robert Jr Laforce, CHU de Québec - Université Laval
Matthis Synofzik, Hertie-Institut für klinische Hirnforschung
James B. Rowe, Cambridge University Hospitals NHS Foundation Trust
Elizabeth Finger, Western UniversityFollow
Rik Vandenberghe, Leuven Brain Institute
Christopher R. Butler, University of Oxford Medical Sciences Division
Alexander Gerhard, The University of Manchester
John C. Van Swieten, Erasmus MC
Harro Seelaar, Erasmus MC
Barbara Borroni, Università degli Studi di Brescia
Daniela Galimberti, Ospedale Maggiore Policlinico Milano
Alexandre De Mendonça, Faculdade de Medicina, Universidade de Lisboa
Mario Masellis, University of Toronto
M. Carmela Tartaglia, Tanz Centre for Research in Neurodegenerative Diseases

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Journal of Neurology, Neurosurgery and Psychiatry





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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.