Research Group Oliver Distler

SSc encompasses from very early stages (veSSc, patients at risk of SSc) to severe, life-threatening forms with multiple organ involvement. The disease course varies significantly, ranging from relatively stable to rapidly progressive. Currently, treatment typically begins only after considerable organ damage and patient burden have already occurred. With this study, we aim to lay the foundation for shifting the treatment paradigm towards prevention, addressing damage and patient burden before they manifest. Our primary objectives are to:

1. Define the target population among pre-SSc patients at high risk of progressing to severe SSc.
2. Identify molecular and cellular targets for early therapeutic intervention.

For Objective II, we are performing high-throughput molecular mapping of pre-SSc, employing single-cell RNA sequencing (scRNA-seq) on skin and cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) on PBMCs. Newly identified targets will undergo functional characterization in 2D and 3D cultures, as well as precision-cut tissue slices, followed by validation in vivo using established SSc mouse models.

Spontaneous regression of skin fibrosis occurs in many systemic sclerosis patients with a short disease duration and extensive skin involvement, even under standard care. However, the molecular mechanisms driving this natural resolution of fibrosis remain unexplored. Our overarching aim is to identify molecular mediators and mechanisms involved in this spontaneous regression, which could serve as potential therapeutic targets to promote fibrosis resolution in cases of stable or progressive disease.

We are performing high throughput screenings in skin biopsies, peripheral blood mononuclear cells (PBMCs) and serum of SSc patients. After 12 months, the patients are classified as progressors, stable or regressors. By comparing baseline differences across these groups using scRNA-seq, proteomics, and spatial transcriptomics, we will generate a comprehensive, multilevel molecular and cellular landscape defining skin fibrosis regression. In vitro, gain- or loss-of-function experiments will be performed to assess the impact of target modulation on fibrosis. We will also evaluate the effects of candidate targets on fibrosis in precision-cut skin slices. In vivo studies will include the use of the bleomycin-induced skin fibrosis model and the tight-skin-1 (Tsk-1) mouse model. These experiments will round out the preclinical assessment of the most promising therapeutic targets.

The role of the immune system in SSc pathogenesis remains unclear. Recent transcriptomic data hinted at a prominent involvement of the immune compartment. The aim of this study is to investigate alterations of the circulating immune cell in SSc patients. We are performing CITE-seq on healthy and SSc PBMCs to characterize altered molecular and cellular processes in systemic sclerosis.

Long non-coding RNAs (lncRNAs) are a recently emerging class of important gene regulators mediating their effects via a wide variety of mechanisms. LncRNAs are thought to be higher in numbers than coding RNAs, underlining their potential as master regulators of biological pathways and mediators of diseases. However, little is known about the role of lncRNAs in fibrotic diseases. We hypothesize that lncRNAs might be key drivers in the pathophysiology of fibrosis in SSc. Here, we aim to identify uncharacterized lncRNAs using different screening technique like whole genome RNA sequencing, scRNA-seq, or RT-qPCR on SSc vs healthy skin biopsies or fibroblasts. Furthermore, we aim to define the fibrotic molecular cascades that trigger lncRNAs dysregulation. In parallel, using gain and loss of function technologies and functional assay, we will address the role of the newly identified lncRNAs. High-throughput and cutting-edge technlologies like ATAC-seq, ChiRP or RNA pull down will be use to asses lncRNAs interactome and define the molecular mechanism of action.

We are conducting high-throughput screening assays of tool compounds for systemic sclerosis (SSc) and fibrosis. A key hallmark of SSc fibroblasts is their differentiation into highly activated α-smooth muscle actin (α-SMA)-positive myofibroblasts, which secrete large amounts of extracellular matrix components. Transforming growth factor beta (TGF-β) has been identified as a primary driver of fibroblast activation into myofibroblasts during the early, active phase of the disease. In this study, large compound libraries are screened on SSc fibroblasts using an automated platform to assess their ability to inhibit myofibroblast differentiation. The endpoint is determined through immunofluorescence staining for the myofibroblast marker α-SMA. Further characterization of candidate anti-fibrotic compounds will also be conducted