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

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cam.issuedOnline2022-04-04
datacite.isderivedfrom.doi10.1101/2021.12.14.21267456
dc.contributor.authorWilson, Katherine M
dc.contributor.authorKatona, Eszter
dc.contributor.authorGlaria, Idoia
dc.contributor.authorCarcolé, Mireia
dc.contributor.authorSwift, Imogen J
dc.contributor.authorSogorb-Esteve, Aitana
dc.contributor.authorHeller, Carolin
dc.contributor.authorBouzigues, Arabella
dc.contributor.authorHeslegrave, Amanda J
dc.contributor.authorKeshavan, Ashvini
dc.contributor.authorKnowles, Kathryn
dc.contributor.authorPatil, Saurabh
dc.contributor.authorMohapatra, Susovan
dc.contributor.authorLiu, Yuanjing
dc.contributor.authorGoyal, Jaya
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorLaforce, Robert Jr
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorRowe, James B
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorVandenberghe, Rik
dc.contributor.authorButler, Christopher R
dc.contributor.authorGerhard, Alexander
dc.contributor.authorVan Swieten, John C
dc.contributor.authorSeelaar, Harro
dc.contributor.authorBorroni, Barbara
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorde Mendonça, Alexandre
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, M Carmela
dc.contributor.authorOtto, Markus
dc.contributor.authorGraff, Caroline
dc.contributor.authorDucharme, Simon
dc.contributor.authorSchott, Jonathan M
dc.contributor.authorMalaspina, Andrea
dc.contributor.authorZetterberg, Henrik
dc.contributor.authorBoyanapalli, Ramakrishna
dc.contributor.authorRohrer, Jonathan D
dc.contributor.authorIsaacs, Adrian M
dc.contributor.authorGenetic FTD Initiative (GENFI)
dc.contributor.orcidCarcolé, Mireia [0000-0001-5054-9016]
dc.contributor.orcidHeller, Carolin [0000-0002-1934-6162]
dc.contributor.orcidSynofzik, Matthis [0000-0002-2280-7273]
dc.contributor.orcidRowe, James B [0000-0001-7216-8679]
dc.contributor.orcidFinger, Elizabeth [0000-0003-4461-7427]
dc.contributor.orcidGerhard, Alexander [0000-0002-8071-6062]
dc.contributor.orcidVan Swieten, John C [0000-0001-6278-6844]
dc.contributor.orcidSeelaar, Harro [0000-0003-1989-7527]
dc.contributor.orcidBorroni, Barbara [0000-0001-9340-9814]
dc.contributor.orcidGalimberti, Daniela [0000-0002-9284-5953]
dc.contributor.orcidDucharme, Simon [0000-0002-7309-1113]
dc.contributor.orcidSchott, Jonathan M [0000-0003-2059-024X]
dc.contributor.orcidZetterberg, Henrik [0000-0003-3930-4354]
dc.contributor.orcidRohrer, Jonathan D [0000-0002-6155-8417]
dc.contributor.orcidIsaacs, Adrian M [0000-0002-6820-5534]
dc.date.accessioned2022-04-07T10:00:48Z
dc.date.available2022-04-07T10:00:48Z
dc.date.issued2022-07
dc.date.submitted2021-12-21
dc.date.updated2022-04-07T10:00:48Z
dc.descriptionFunder: Bluefield Project
dc.descriptionFunder: Fidelity Foundation; FundRef: http://dx.doi.org/10.13039/100005639
dc.descriptionFunder: European Reference Network for Rare Neurological Diseases
dc.descriptionFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100010269
dc.descriptionFunder: EU Joint Programme - Neurodegenerative Disease Research
dc.description.abstractOBJECTIVE: 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.
dc.identifier.citationJournal of Neurology, Neurosurgery, and Psychiatry, page jnnp-2021-328710
dc.identifier.doi10.17863/CAM.83297
dc.identifier.eissn1468-330X
dc.identifier.issn0022-3050
dc.identifier.otherjnnp-2021-328710
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335864
dc.languageen
dc.language.isoeng
dc.publisherBMJ
dc.publisher.urlhttp://dx.doi.org/10.1136/jnnp-2021-328710
dc.subjectFRONTOTEMPORAL DEMENTIA
dc.subjectMOTOR NEURON DISEASE
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectBiomarkers
dc.subjectC9orf72 Protein
dc.subjectDNA Repeat Expansion
dc.subjectFrontotemporal Dementia
dc.subjectHumans
dc.titleDevelopment of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
dc.typeArticle
dcterms.dateAccepted2022-03-04
prism.publicationNameJ Neurol Neurosurg Psychiatry
pubs.funder-project-idNational Institute for Health and Care Research (IS-BRC-1215-20014)
pubs.funder-project-idMedical Research Council (MC_U105597119)
pubs.funder-project-idMedical Research Council (MC_UU_00005/12)
pubs.funder-project-idWellcome Trust (220258/Z/20/Z)
pubs.funder-project-idMRC (MC_UU_00030/14)
rioxxterms.freetoread.startdate2022-04-04
rioxxterms.licenseref.startdate2022-04-04
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1136/jnnp-2021-328710

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