Diethysuccinate as a novel therapeutic for IPF

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease where healthy lung tissue is replaced by scar tissue. This is accompanied by a steady deterioration in lung function and ultimately leads to respiratory failure and death. Although lung transplantation is an option, there is only a limited number of suitable donor lungs available, and not all patients are eligible for this procedure. Currently, there are only two approved drugs that can slow the disease progression, but they are not curative and do not improve survival. Diethyl succinate (DES) is a chemical modification of succinate which, unlike the latter, is able to penetrate cell membranes. This project aims to clarify whether DES has antifibrotic effects and how these are mediated. To answer this question, we will conduct a series of experiments. We will treat lung fibroblasts- the cells that form scar tissue- isolated from IPF patients with DES and examine whether this leads to a normalization of these cells and to a healthier behaviour (e.g. reduced collagen secretion). In addition, we will also test the effects of DES in other cells that may also contribute to the development of fibrosis. We will also investigate whether DES can lead to relevant improvements in explanted lungs from fibrosis patients. In further experiments, we will test whether DES can also exert an antifibrotic effect in animal models. This is necessary because immune cells that have migrated from the blood are also thought to be involved in the development of fibrosis, and this cannot be adequately investigated in explanted lungs. Since DES has not been sufficiently characterized, we will also investigate its tolerability and the most important route of excretion and its metabolization in the organism. In addition, we will test cells and lung tissue from other fibrotic lung disease, to see whether DES effects are restricted to IPF or rather represent a general antifibrotic mechanism. Overall, the project therefore aims to establish a new therapeutic molecule in pulmonary fibrosis and to characterize it as precisely as possible.