Differential Diagnosis of Autoimmune Hepatitis by cfChIP-seq Liquid Biopsy

Projektbeschreibung

DNS-basierte Flüssigbiopsie zur Lebererkrankungsdiagnose

Die genaue Ermittlung der Ursachen von Lebererkrankungen ist für eine wirksame Behandlung von entscheidender Wichtigkeit. Die Unterscheidung zwischen Autoimmunhepatitis, medikamenteninduzierter Leberschädigung und weiteren nichtviralen Lebererkrankungen bleibt jedoch schwierig. Die Diagnose einer Autoimmunhepatitis umfasst typischerweise eine Kombination aus Bluttests auf spezifische Autoantikörper, Leberfunktionstests und oftmals einer Leberbiopsie, um das Vorhandensein von Entzündungen und autoimmuner Aktivität zu bestätigen. Das Hauptziel des ERC-finanzierten Projekts AIHLiquidBiopsy besteht darin, invasive Leberbiopsien durch eine minimalinvasive Flüssigbiopsie zu ersetzen. Mit der vorgeschlagenen Technologie werden epigenetische Markierungen in zellfreier DNS aus Blutproben analysiert. Auf diese Weise werden Kartierungen der genomweiten Genaktivität im Zusammenhang mit Leberschäden und Differenzialdiagnosen von Lebererkrankungen möglich.

Ziel

The identification of the causative agent and mechanism of liver disorders is essential for effective treatment. The diagnostic challenge is differentiating autoimmune hepatitis, drug induced liver damage, and other non-viral causes of liver disease. Current diagnostic guidelines require in many cases liver biopsy followed by monitoring response to treatment before conclusive diagnosis. Our objective is to replace liver biopsy in the parenchymal liver disease settings with a minimally invasive liquid biopsy from a blood sample.

We have developed cfChIP-seq, a liquid biopsy that enables detection of gene activity in the cells contributing to cell-free DNA. Cell-free DNA is mostly chromatin fragments DNA-protein complexes. These carry post-translational epigenetic marks that are closely connected to gene regulation and activity in the cell of origin. By capturing fragments marked with active transcription and sequencing their DNA, we map genome-wide activity of genes in the cells contributing to circulating cell-free DNA.

Liver damage results in increased contribution of liver cells to circulating cell-free DNA. Moreover, our preliminary results show that we can detect differences in the cfChIP-seq signal from different liver pathologies and that these differences involve genes associated with the relevant liver damage mechanisms.

We plan to develop methods for differential diagnosis of autoimmune liver diseases such as autoimmune hepatitis and other parenchymal liver diseases. This will be supplemented by a multi-center cohort of patients to train and validate these tools. Together these will establish a pre-clinical evaluation of the capabilities of the assay in differential diagnosis and enable development of a product that would change the way we diagnose these diseases. This product will improve the quality of diagnosis, reduce the number of liver biopsies, risk to patients and costs, and provide more detailed follow-up during treatment.