Open Research Projects, Research

Circulating cell-free DNA as biomarker for prognosis and treatment response in psoriasis

Principle Investigator

Prof. Dr. Kamran Ghoreschi
Dr. Franz Hilke

Scientific interest within the context of the graduate college:

Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and also preventive medicine. One of our translational research interests are chronic inflammatory autoimmune diseases of the skin. In addition to preclinical models and in vitro methods, we use skin and blood samples from patients for biomarker identification. We are particularly interested in specialized T cell responses, cytokine signaling pathways and the application of liquid biopsy in chronic inflammatory skin diseases.

Project description:

Introduction: Cell-free DNA (cfDNA) refers to DNA fragments that are found in body fluids, such as blood. In psoriasis, the release of DNA from damaged skin cells into the bloodstream is an active field of research for the implementation as a potential biomarker.1-3 Thus, cfDNA may carry information about the inflammatory processes and cellular damage occurring in the skin.

The field of biomarkers in psoriasis is broad and continually evolving, with scientists aiming to identify reliable markers that can help in diagnosis, prognosis, treatment response assessment, and understanding the underlying mechanisms of the disease. We are interested in the physical and molecular features of cfDNA fragments to study treatment response and reconstitution of health.

Aims: The research project aims to validate the possibilities and limitations of cfDNA in psoriasis. This includes the quantification of cfDNA in the plasma of psoriasis patients as a marker for increased cellular turnover. The determination of the absolute copy number of psoriasis-associated genes of inflammatory activity (TNFa, IL17A/F, IL23, IL6) and epidermal activity (KRT16, KRT6, KRT17) as markers for disease activity. Within the framework of the doctoral project, patients with an active disease before the initiation of therapy are examined as well as those undergoing therapy (therapy responders and non-responders). The investigations are carried out in comparison with control subjects without inflammatory or autoimmune skin disease, or any other chronic disease such as cancer.

In addition, we aim to improve an assay that can accurately determine the amount of cfDNA originating from epidermal keratinocytes. For this purpose, the methylation of cfDNA from psoriasis patients and age- and sex-matched controls will be analyzed. With the help of the methylation atlas by Zhu et al. (Nat Methods, 2022)4 and Loyfer et al. (Nature, 2023)5 and is possible to perform a deconvolution of cfDNA that allows the composition with regard to the tissue origin.

The doctoral thesis is embedded in a pilot study that examines 20 controls and 120 patients with psoriasis as proof of concept. The focus of the doctoral thesis is the definition of qualitative and quantitative differences of cfDNA in psoriasis patients and healthy individuals, as well as treatment responders and non-responders. The overall goal is to validate the possibilities and limitations of cfDNA as a biomarker for disease activity, treatment response and flare prognosis in psoriasis.

References

  1. Sakamoto R, Sawamura S, Kajihara I, Miyauchi H, Urata K, Otsuka-Maeda S, […], Makino T, Fukushima S, Ihn H. Circulating tumor necrosis factor-α DNA are elevated in psoriasis. J Dermatol. 2020; 47(9):1037-1040.
  2. Wiggins, J, Ali S, Polsky D. Cell-Free DNA in Dermatology Research. J Invest Dermatol. 2022; 142(6):1523-1528.e1.
  3. Beranek M, Fiala Z, Kremlacek J, Andrys C, Krejsek J, Hamakova K, Chmelarova M, Palicka V, Borska L. Changes in circulating cell-free DNA and nucleosomes in patients with exacerbated psoriasis. Arch Dermatol Res. 2017; 309(10):815-821.
  4. Zhu T, Liu J, Beck S, Pan S, Capper D, Lechner M, Thirlwell C, Breeze CE, Teschendorff AE. A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. Nat Methods. 2022; 19(3):296-306.
  5. Loyfer N, Magenheim J, Peretz A, Cann G, Bredno J, Klochendler A, […], Dor Y, Glaser B, Kaplan T. A DNA methylation atlas of normal human cell types. Nature. 2023; 613(7943):355-364.