Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
Authors
Wilson, Katherine M
Katona, Eszter
Glaria, Idoia
Swift, Imogen J
Sogorb-Esteve, Aitana
Bouzigues, Arabella
Heslegrave, Amanda J
Keshavan, Ashvini
Knowles, Kathryn
Patil, Saurabh
Mohapatra, Susovan
Liu, Yuanjing
Goyal, Jaya
Sanchez-Valle, Raquel
Laforce, Robert Jr
Vandenberghe, Rik
Butler, Christopher R
de Mendonça, Alexandre
Masellis, Mario
Tartaglia, M Carmela
Otto, Markus
Graff, Caroline
Malaspina, Andrea
Boyanapalli, Ramakrishna
Genetic FTD Initiative (GENFI)
Publication Date
2022-07Journal Title
J Neurol Neurosurg Psychiatry
ISSN
0022-3050
Publisher
BMJ
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Wilson, K. M., Katona, E., Glaria, I., Carcolé, M., Swift, I. J., Sogorb-Esteve, A., Heller, C., et al. (2022). Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.. J Neurol Neurosurg Psychiatry https://doi.org/10.1136/jnnp-2021-328710
Description
Funder: Bluefield Project
Funder: Fidelity Foundation; FundRef: http://dx.doi.org/10.13039/100005639
Funder: European Reference Network for Rare Neurological Diseases
Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100010269
Funder: EU Joint Programme - Neurodegenerative Disease Research
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.
Keywords
Neurodegeneration, 1506, FRONTOTEMPORAL DEMENTIA, MOTOR NEURON DISEASE
Sponsorship
National Institute for Health Research (IS-BRC-1215-20014)
Identifiers
jnnp-2021-328710
External DOI: https://doi.org/10.1136/jnnp-2021-328710
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335864
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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