eRapport

ABC-AD: ABC transporters as early diagnostics and treatment marker for neurodegenerative dementias – towards a personalised medicine in dementia

Prosjekt
Prosjektnummer
2016062
Ansvarlig person
Jens Pahnke
Institusjon
Oslo universitetssykehus HF
Prosjektkategori
Postdoktorstipend
Helsekategori
Mental Health, Neurological
Forskningsaktivitet
2. Aetiology, 4. Detection and Diagnosis
Rapporter
2018 - sluttrapport
ABC transporters have been discovered to play a major role in the pathogenesis of neurodegenerative diseases with protein deposition. Especially, transporters at the blood-brain barrier are needed to excrete toxic metabolites from the brain into the blood stream. Till now, it was not clear to which extent the export is contributing to the prevention of protein aggregation and whether or not families exist that have a familiar form of any neurodegenerative disease and mutations/ specific genetic conditions in one of the ABC transporter genes. So far, ABCA1, A7, B1, C1, and G2 are regarded to serve as exporters with different specificity. We were able to describe ABCC1 as one major exporter in Alzheimer's disease, responsible for Abeta export. Additionally, ABCB1 and the low-density lipoprotein receptor 1 work together as an export chain from astrocyte endfeet towards endothelia in the wall of capillaries. Aims of the project were: 1. Detect therapy and diagnostic relevant genetic changes in ABC transporter loci of patients with neurodegenerative diseases; 2. Map changes with clinical outcome of patients (age of onset, risk in family, disease course); 3. Detect changes that are relevant for ABC transporter activating therapies (effect prognostics); 4. Establish genetic markers for sub-cohorts. We applied for funding for chemicals and reagents for the sequencing analysis and for a supporting PostDoc position. We got funding for the position. Funding for reagents was refused. This unexpected stupidity was causing severe headache who we might able to perform the proposed analyses. Therefore, the analyses had to be performed in Germany at our collaborators labs together with external funding from Germany. The HSØ-funded position supported the analytical studies with our previously collected patient cohort from the University of Magdeburg. Because of the lack of financial support for the analytics, patients from Norway or relatives could not be prioritised. Despite all caveats, we are now able to describe relevant changes in the ABCC1 gene that lead to dementia and deposition of Abeta in patients/ familiar AD. These genetic changes support the hypothesis that was established in 2004, that ABC transporters modulate and can be causative for neurodegenerative diseases. The DRAIN-AD study that was performed in 2018 by our collaborator Prof. Jens Wiltfang at the Psychiatric clinics of the University of Gottingen proved that ABCC1-activation by thiethylperazine facilitates the export of beta-amyloid moieties from the cerebrospinal fluid into the blood stream with a peak efflux at 28 hours after drug application. The mechanism was patented in 2010 by inventor Jens Pahnke/ Univ. of Rostock and is exclusively licensed to Immungenetics AG/ Rostock in Germany. Immungenetics AG was the exclusive sponsor of this treatment study. Herewith, we can declare our project a full success, also with the knowledge that a submitted publication will show the first family from Phoenix (AZ, USA) with an ABCC1 mutation, clinical fronto-temporal-dementia (FTD) and autopsy confirmed histological Alzheimer amyloidosis. In future, it will be needed to sequence ABC transporter genes in patients with neurodegenerative diseases. The information gathered will enable patient-directed therapies that become available.

NO

2017
Currently early diagnostics and treatment of dementia is not securely available. We have discovered that ABC transporters play a fundamental role in excreting toxic peptides from the brain and that this mechanism can be used for diagnostics and treatment. It was confrmed in elderly having reduced transbarrier clearance at the blood-brain barrier.The project was presented at the TransportDEMENTIA 3 meeting in September in Svolvær on the Lofoten Islands. Here we discussed various components of the analysis of ABC transporter loci and the mitochondrial genome together with our international colleages that gathered at this occasion. Those how could not come in person were connected via Skype. For more information please refer to: http://pahnkelab.eu/transportdementia-meetings/ where a full report of the meeting is available. Our international collaborators from Amsterdam (James Milles) presented new methods for computational analysis of next-genome-sequencing data which are highly important for our approach. Using information from our previoous studies, a phase IIb treatment study was started in Germany in November at the University of Göttingen / Department of Psychiatry. It is planned to include 7 patients with early dementia as 7 age-matched relatives as controls in this first phase of this treatment study. The study tests a known drug (EMA approved) that activates the ABCC1 transporter. The result o this study will enable us to verify whether or not this mechanism is clinically important for diagnostics and treatment. We hope that our Oslo project can deliver more information in 1-2 years to be able to stratify patients for such studies. We closely work together with the Department of Genetics at the University of Tübingen (Prof. Olaf Riess) who performs the NGS analysis for us since we got no funding from HSØ to perform these in Oslo. We use our German cohort to succeed with these analyses. To gather additional funding we applied together with several international groups (17) at the latest IMIc12t6 EU call which aimed on blood-brain barrier function.

nei

2016
Currently early diagnostics and treatment of dementia is not securely available. We have discovered that ABC transporters play a fundamental role in excreting toxic peptides from the brain and that this mechanism can be used for diagnostics and treatment. It was confirmed in elderly having reduced transbarrier clearance at the blood-brain barrier.The project focuses on deciphering genomic alterations in ABC transporter genes with respect to type of neurodegenerative / neuroinflammatoy disease, onset of disease and also possible treatment effects of ongoning treatment in the patients. Additionally, we integrate data about the circumstances of living and the progression of disease. We investigate ABC transporter loci of an excisting and clinically characterized cohort of neurodegenerative diseases in Magdeburg / Germany. Our goal is to detect changes in the genomic arrangement in the ABC transporter loci, mitochondria and binding miRNA with sporadic forms of the diseases. Since we have not been granted money for the financing of the chemicals for sequencing as applied for, we have been submitting additional grants (as suggested by HSØ) again for the sole financing of the chemicals for library generation and next-genome sequencing. Unfortunately, we did not receive funding in the recent round (note from Dec 2016) and also no additional hints why not. As we have been stating before it is essential for the project to finance the chemicals/consumables. To grant a position for research without granting the consumables is nice, but is not sufficient for projects that indeed rely on new and expensive methods, especially if a larger cohort needs to be fully analysed for statistical reasons. To overcome these caveats we have been starting with the setup of confirmation assays and as proposed by one of the reviewers before with possiblilities to check the results in model organisms. Herefore, we established also assays from primary vessel cells / endothelia and pericytes/ from humanised animals to be able to set up a method for in vitro analyses. Humanized animals enable us the directly control for a human gene function/ alteration in an animal background which is thought to be more realistic with respect to later clinical use that the sole transgene or knockout models. The availaible models represent 3 ABC human transporters and are currently checked for the right expression distribution.
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Deltagere
  • Thomas Brüning Prosjektdeltaker
  • Kristin Paarmann Forsker (annen finansiering)
  • Markus Krohn Forsker (annen finansiering)
  • Mirjam Brackhan Postdoktorstipendiat (finansiert av denne bevilgning)
  • Jens Pahnke Prosjektleder

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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