期刊
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
卷 -, 期 -, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jnnp-2021-328710
关键词
FRONTOTEMPORAL DEMENTIA; MOTOR NEURON DISEASE
资金
- Wave Life Sciences
- European Research Council (ERC) under the European Union [648716 -C9ND]
- UK Dementia Research Institute from UK DRI
- Alzheimer's Society
- Alzheimer's Research UK
- Brain Research UK
- Wolfson Foundation
- NIHR UCL/H Biomedical Research Centre
- Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- Weston Brain Institute
- Selfridges Group Foundation award [UB170045]
- Engineering and Physical Sciences Research Council [EP/J020990/1]
- British Heart Foundation [PG/17/90/33415]
- EU [666992]
- Wellcome Trust
- Fidelity International Foundation
- UK DRI
- Miriam Marks Brain Research UK Senior Fellowship
- MRC Clinician Scientist Fellowship [MR/M008525/1]
- NIHR Rare Disease Translational Research Collaboration [BRC149/NS/MH]
- MRC UK GENFI grant [MR/M023664/1]
- Bluefield Project
- JPND GENFI-PROX grant [2019-02248]
- European Reference Network for Rare Neurological Diseases [739510]
- UK Medical Research Council
This study developed a highly sensitive and robust immunoassay for measuring poly(GP) dipeptide repeat proteins in the cerebrospinal fluid of patients with C9orf72-associated FTD/ALS. The assay showed 100% specificity and sensitivity, and is suitable for use in clinical trials to determine target engagement.
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.
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