PET analyses of ABC transporter function for diagnostics and stratification of dementia patients
Support provider:
The Ministry of Education, Youth and Sports of the Czech Republic
Funded:
The EU Joint Programme – Neurodegenerative Disease Research (JPND)
Investigator:
Norway, Prof. Jens PAHNKE, University of Oslo (UiO)/Oslo University Hospital (OUS)
Germany, Prof. Peter BRUST, Helmholtz Zentrum, Dresden-Rossendorf (HZDR), LeipzigAustria, Prof. Oliver LANGER, Medical University of Vienna (MUV), Vienna
Latvia, Prof. Baiba JANSONE, University of Latvia (LU),Rīga
Czech, Prof. Ondřej SOUKUP, University Hospital Hradec Králové
France, Prof. Fabien GOSSELET, Université d’Artois, Lens
Sweden, Prof. Henrik BIVERSTÅL, Karolinska Institutet (KI), Stockholm
Abstract:
The blood-brain barrier (BBB) expresses different ATP-binding cassette (ABC) transporters, which control the access of endogenous and exogenous compounds from the blood into the brain as well as their removal from the brain into the blood. The export function of the BBB is of increasing importance and is moving continuously into the focus of research on neurodegenerative diseases (NDs). We have described for the first time that the ABC transporter C1 (ABCC1) is exceptionally important for the export of metabolites from the brain, especially for amyloid-β (Aβ) The aim to translate our new ABCC1 PET protocol to AD patients to assess whether cerebral ABCC1 function is impaired in comparison to age-matched healthy control subjects and to investigate the relevance of ABCC1 for the diagnostics of functional BBB-deficiency, which will allow better classification of patient groups. In parallel, we will extend our efforts toward ABCA7 and aim at developing the first PET radiotracers for imaging of ABCA7. These efforts will comprise several in vitro and in vivo investigations by using human and mouse cell culture BBB models (hPSC/iPSC-based and with specific knockout endothelia), humanized mouse models, chemical synthesis of new ABCA7 probes, morphological/toxicology analyses, ssNMR/cryo-EM, radiolabeling methods, and animal PET imaging. Following a precision medicine approach, the segregation of disease diagnoses/sub-diagnoses based on ABC transporter function may potentially enable targeted treatment studies for those patients who show transport deficiency. Moreover, the assessment of ABC transporter function may potentially allow for the stratification of patient populations for preventive interventions.
Project duration:
2021–2023
Targeted and Improved Alzheimer's Disease Drug Development
Support provider:
Technology Agency of the Czech Republic KAPPA Programme
Funded:
EEA grants
Norway grants
Investigator:
Main investigator:
University hospital Hradec Kralove, Czech Republic - assoc. prof. Ondrej Soukup, Ph.D.
Other investigators:
University of Oslo - Prof. Dr. med. Dr. rer. nat. Jens Pahnke E.F.N.
Institute of Experimental Medicine CAS - Mgr. Martin Horak Ph.D.
Bioinova, s.r.o. - MUDr. Peter Bauer Ph.D.
Abstract:
The aim of the project is the development of compounds for the treatment of Alzheimer´s disease (AD). The project will include an approaches of personalized medicine during the development process in the way that novel compounds will be tested in a disease in a dish (DiD) model derived from AD patients.
Project duration:
January 2021–April 2024
