HYMAGE-IPF

Description of the disease and state of knowledge: Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung of unknown aetiology with a median survival time of less than five years. Treatment options are limited with only two approved drugs, nintedanib and pirfenidone, which demonstrate efficacy to slow down fibrosis progression but are unable to reverse or stop the disease. Currently, tools to monitor the efficacy of these therapies are inexistent. IPF is characterized by a TGFß1-dependant proliferation of myofibroblasts responsible for the aberrant accumulation of extracellular-matrix (ECM) in the lungs. Chronic hypoxia of the lung is a significant clinical feature of patients with IPF but its exact role on the progression of the disease remains elusive. At the cellular level, hypoxia signalling is mainly mediated by the upregulation of HIF-1a which is involved in myofibroblast differentiation. Hypoxic area are found in the IPF lung and hypoxia exposure exacerbates lung fibrosis in animal models. Hypoxia promotes the alternative activation of macrophages into a so called M2 phenotype characterized by the expression of the CD206 receptor and the production of profibrotic mediators such as TGF-ß1. Secreted heat shock protein (HSP)-90 and low density lipoprotein-related protein receptor (LRP1) are involved in M2 polarisation in hypoxic condition. Our preliminary data demonstrate that 1/ imaging of hypoxia with the PET tracer 18F-FMISO correlates with lung fibrosis in preclinical models, 2/ imaging of M2 macrophages with the SPECT tracer 99mTc-Tilmanocept (targeting CD206) demonstrate infiltration of fibrotic lungs by these pro-fibrotic macrophages, 3/ M2 macrophages are detectable by 99mTc-Tilmnaocept SPECT imaging in area that appear “normal” of CT-scans of fibrotic lungs, 4/ LRP1 is upregulated in lung fibroblasts from IPF patients, 5/ secreted HSP90 interacts with LRP1 to activate pro-fibrotic signalling promoting IPF progression and 6/ inhibition of LRP1 abrogated pro-fibrotic signals mediated by secreted HSP90. Objectives: 1/ to evaluate the therapeutic efficacy of the blocking of hypoxia signalling via inhibition of HIF1a, secreted HSP90 and LRP1 in experimental fibrosis. 2/ to develop and evaluate imaging probes targeting hypoxia and hypoxia signalling (M2 macrophages and LRP1) to detect/quantify lung fibrosis in preclinical models and 3/ to evaluate the efficacy of the developed probes to monitor the efficacy of existing anti-fibrotic therapies (nintedanib and pirfenidone) as well as novel anti-fibrotic therapies (anti-HIF1a, anti-LRP1 and anti-sHSP90) in preclinical models. Description of the project methodology: 1/ Specific inhibition of HIF1a, secreted HSP90 or LRP1 will be investigated in vitro in normoxia and hypoxia on myofibroblasts differentiation and macrophage polarization on murine lung epithelial cells/fibroblasts and primary human monocytes and in vivo in our animal models, 2/ Hypoxia, M2 macrophage and LRP1 imaging will performed by PET or SPECT after i.v. injections of the 18F-FMISO, 99mTc-Tilmanocept or a LRP1 antagonist, RAP, radiolabelled with the SPECT isotope 111In in our animal models and 3/ the impact of HIF1a, secreted HSP90 or LRP1 inhibition and pirfenidone/nintedanib on Hypoxia, M2 macrophage and LRP1 imaging will be evaluated in our animal models. Expected results and impacts: This project will allow supporting whether or not, hypoxia and its signalling through LRP1 and M2 macrophages polarisation could be surrogate imaging biomarkers for IPF. We believe that the development of innovative tools for the detection of specific biological pathways involved in pulmonary fibrosis will be a first step in the development of personalized therapies for IPF patients, which is currently unavailable. Our ambitious project will therefore promote the development of targeted therapies based on hypoxia inhibition which are inexistent for in IPF.