Moderator of 1 Session
Presenter of 1 Presentation
TMTCALIBRATOR - COMBINED TISSUE AND FLUID PROTEOMICS SUPPORTS DECISION MAKING IN AN ALZHEIMER’S DISEASE CLINICAL TRIAL PROGRAM
Abstract
Aims
Accepted biomarkers related to CSF Aβ and pTau lack insight for novel therapeutic strategies related to up- and down-stream biological pathways and processes. We have demonstrated the power of unbiased hybrid tissue/fluid proteomics to deliver biomarkers relevant to a novel mechanism of action that can guide decisions in later phases of clinical trials.
Methods
CSF (0.5 ml) from patients before and after 12 weeks treatment with Xpro at three different doses was analyzed using TMTcalibrator™ (Figure 1) where inclusion of high levels of TMTpro™-labelled AD brain cortex lysate with similarly labelled digests of CSF is used to boost sensitivity for disease-relevant peptides during mass spectrometry analysis. Off-line phosphopeptide enrichment and fractionation was combined with tandem mass spectrometry and sophisticated bioinformatics to identify biomarker sets relating to different aspects of disease modulated by Xpro treatment.
![tmtpro workflows [autosaved].png](https://s3.eu-central-1.amazonaws.com/eu-cpaper-prod/mediafiles/adpd_22/0000001094/000454.png "tmtpro workflows [autosaved].png")
Results
Overall, 37,018 peptides associated with 4,966 protein groups and 5,202 individual phosphorylation sites were quantified. Functional analysis showed that treatment-responsive CSF proteins from a wide range of disease-relevant biological processes and pathways related to neuronal organization, synaptic function, immune and inflammatory response, cytoskeleton, metabolism, Rho GTPases signalling, and myelination. Notably, 12 weeks high-dose treatment led to decreased expression of several emerging neuronal markers - NFL↓84%; Tau pT217↓46%; Neurogranin ↓56% and increased for myelin regulatory factor ↑25%. We will show how these and other results are guiding design of Phase II studies during the presentation.
Conclusions
Unbiased proteomics revealed both known and unexpected effects of Xpro through measurement of CSF proteins and these panels will guide our future studies.