Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Issue 7 (4th April 2022)

• Record Type: Journal Article
• Authors: Wilson, Katherine M; Katona, Eszter; Glaria, Idoia; Carcolé, Mireia; Swift, Imogen J; Sogorb-Esteve, Aitana; Heller, Carolin; Bouzigues, Arabella; Heslegrave, Amanda J; Keshavan, Ashvini; Knowles, Kathryn; Patil, Saurabh; Mohapatra, Susovan; Liu, Yuanjing; Goyal, Jaya; Sanchez-Valle, Raquel; Laforce, Robert Jr; Synofzik, Matthis; Rowe, James B; Finger, Elizabeth; Vandenberghe, Rik; Butler, Christopher R; Gerhard, Alexander; Van Swieten, John C; Seelaar, Harro; Borroni, Barbara; Galimberti, Daniela; de Mendonça, Alexandre; Masellis, Mario; Tartaglia, M Carmela; Otto, Markus; Graff, Caroline; Ducharme, Simon; Schott, Jonathan M; Malaspina, Andrea; Zetterberg, Henrik; Boyanapalli, Ramakrishna; Rohrer, Jonathan D; Isaacs, Adrian M;
• Other Names: author non-byline.; Afonso Sónia author non-byline.; Almeida Maria Rosario author non-byline.; Anderl-Straub Sarah author non-byline.; Andersson Christin author non-byline.; Antonell Anna author non-byline.; Archetti Silvana author non-byline.; Arighi Andrea author non-byline.; Balasa Mircea author non-byline.; Barandiaran Myriam author non-byline.; Bargalló Nuria author non-byline.; Bartha Robart author non-byline.; Bender Benjamin author non-byline.; Benussi Alberto author non-byline.; Bertoux Maxime author non-byline.; Bertrand Anne author non-byline.; Bessi Valentina author non-byline.; Black Sandra author non-byline.; Bocchetta Martina author non-byline.; Borrego-Ecija Sergi author non-byline.; Bras Jose author non-byline.; Brice Alexis author non-byline.; Bruffaerts Rose author non-byline.; Camuzat Agnès author non-byline.; Cañada Marta author non-byline.; Cantoni Valentina author non-byline.; Caroppo Paola author non-byline.; Cash David author non-byline.; Castelo-Branco Miguel author non-byline.; Colliot Olivier author non-byline.; Convery Rhian author non-byline.; Cope Thomas author non-byline.; Danek Adrian author non-byline.; Deramecourt Vincent author non-byline.; Fede Giuseppe Di author non-byline.; Díez Alina author non-byline.; Duro Diana author non-byline.; Fenoglio Chiara author non-byline.; Ferrari Camilla author non-byline.; Ferreira Catarina B. author non-byline.; Fox Nick author non-byline.; Freedman Morris author non-byline.; Fumagalli Giorgio author non-byline.; Funkiewiez Aurélie author non-byline.; Gabilondo Alazne author non-byline.; Gasparotti Roberto author non-byline.; Gauthier Serge author non-byline.; Gazzina Stefano author non-byline.; Giaccone Giorgio author non-byline.; Gorostidi Ana author non-byline.; Graf Lisa author non-byline.; Greaves Caroline author non-byline.; Guerreiro Rita author non-byline.; Hoegen Tobias author non-byline.; Indakoetxea Begoña author non-byline.; Jelic Vesna author non-byline.; Jiskoot Lize author non-byline.; Keren Ron author non-byline.; Kuchcinski Gregory author non-byline.; Langheinrich Tobias author non-byline.; Ber Isabelle Le author non-byline.; Lebouvier Thibaud author non-byline.; Leitão Maria João author non-byline.; Levin Johannes author non-byline.; Lladó Albert author non-byline.; Lombardi Gemma author non-byline.; Lombardi Jolina author non-byline.; Loosli Sandra author non-byline.; Maruta Carolina author non-byline.; Mead Simon author non-byline.; Miltenberger Gabriel author non-byline.; Minkelen Rick van author non-byline.; Mitchell Sara author non-byline.; Moreno Fermin author non-byline.; Nacmias Benedetta author non-byline.; Nelson Annabel author non-byline.; Nicholas Jennifer author non-byline.; Öijerstedt Linn author non-byline.; Papma Janne M. author non-byline.; Pasquier Florence author non-byline.; Peakman Georgia author non-byline.; Pijnenburg Yolande author non-byline.; Polito Cristina author non-byline.; Premi Enrico author non-byline.; Prioni Sara author non-byline.; Prix Catharina author non-byline.; Redaelli Veronica author non-byline.; Rinaldi Daisy author non-byline.; Rittman Tim author non-byline.; Rogaeva Ekaterina author non-byline.; Rosa-Neto Pedro author non-byline.; Rossi Giacomina author non-byline.; Rossor Martin author non-byline.; Santana Isabel author non-byline.; Santiago Beatriz author non-byline.; Saracino Dario author non-byline.; Scarpini Elio author non-byline.; Schönecker Sonja author non-byline.; Shafei Rachelle author non-byline.; Shoesmith Christen author non-byline.; Sorbi Sandro author non-byline.; Tábuas-Pereira Miguel author non-byline.; Tagliavini Fabrizio author non-byline.; Tainta Mikel author non-byline.; Taipa Ricardo author non-byline.; Tang-Wai David author non-byline.; Thomas David L author non-byline.; Thompson Paul author non-byline.; Timberlake Carolyn author non-byline.; Tiraboschi Pietro author non-byline.; Todd Emily author non-byline.; Damme Philip Van author non-byline.; Vandenbulcke Mathieu author non-byline.; Verdelho Ana author non-byline.; Villanua Jorge author non-byline.; Warren Jason author non-byline.; Wilke Carlo author non-byline.; Wlasich Elisabeth author non-byline.; Zulaica Miren author non-byline.;
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 93:Issue 7(2022)
• Page Start: 761
• Page End: 771
• Publication Date: 2022-04-04
• Subjects: FRONTOTEMPORAL DEMENTIA -- MOTOR NEURON DISEASE; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2021-328710
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : 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.