Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
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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, Genetic FTD Initiative (GENFI)
Аннотация
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.