The Vanden Berghe Lab is a multidisciplinary team performing basic as well as applied research on mechanisms, treatment and prevention of cell death-driven diseases, with focus on ferroptosis (kind of biological rust). We follow an integrated approach from knowledge building and discovery to (pre)clinical research, along support and consultancy.
30% of global deaths occur in intensive care units due to multiple organ dysfunction syndrome (MODS). Excess iron is known to cause cell death/ferroptosis and (multi) organ damage in critical illness. In collaboration with Augustyns lab, we developed, characterised and patented ferrostatin-analogues with improved efficacy, solubility and stability. Out of >160 ferrostatin-analogues, two lead candidates with increased solubility were found substantially more stable than Fer1. We have proven the in vivo superior protective action of both lead candidates, over benchmark Fer1 in several ferroptosis-driven experimental disease models. Moreover, one of our lead candidates is lifesaving against acute liver injury, which is unprecedented. We are analysing critical illness patients with MODS for signs of ferroptosis. Novel diagnostic tools are developed to detect ferroptosis and cell death.
The success of transplantation is hampered by a shortage in suitable organ grafts and the adverse effects of ischemia reperfusion injury (IRI). Inflammation and cell death in the transplanted organ, caused by the activation of the innate immune system as part of the IRI process, lead to primary graft dysfunction (PGD). Transplant recipients that suffer from severe PGD have an increased risk for early and late morbidity and mortality.
The ex-vivo organ perfusion strategy was developed to increase the number of available grafts. During the ex-situ phase between organ retrieval and transplantation, machine perfusion offers a unique window of opportunity for organ graft modulation to target ferroptosis due to IRI. Our in-house developed and patented third generation ferroptosis inhibitors show superior protection in preclinical models of organ injury and are therefore good drug candidates to block injury during transplantation.
Neuroblastoma is the most common solid tumor outside the brain of infants and very young children. The aggressive form or high-risk neuroblastoma is characterized by a poor clinical outcome, therapy resistance or even relapse. The challenge is to find new molecular mechanisms to kill the cancer cells. Recently, we discovered a new approach to kill aggressive therapy-resistant neuroblastoma in mice by triggering a sort of biological rusting in cancer cells called ferroptosis. We are developing novel pharmacological and nanomedicinal approaches to improve the therapeutic applicability of ferroptosis in neuroblastoma.
Multiple sclerosis (MS) is an autoimmune disease characterised by central nervous inflammation and demyelination driven by an auto-amplifying mechanism of inflammation and cell death. MS lesions and cerebrospinal fluid of MS patients revealed several signs of ferroptosis. Treatment with our lead ferroptosis inhibitor strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. Stroke is a devastating neurological condition, representing a leading cause of disability and death worldwide. Although stroke is a global health priority, there are still no highly effective acute therapies available. There are quite some indications that ferroptosis also contributes to stroke, therefore the aim of this research project is to explore the therapeutic potential of ferroptosis targeting in stroke.
In patients with sepsis or multi-organ failure syndrome (MODS), plasma labile iron and excessive inflammasome signalling are key detrimental factors associating with mortality. Excess iron is known to cause ferroptosis and organ damage. MODS and sepsis often show substantial individual variation due to genetic differences, co-morbidities, frailty and dynamic disease fluctuations. To deal with this form of heterogeneity, innovative biomarkers with predictive value are needed to allow determining subtypes of clinically similar patients. We use genetic models of ferroptosis-driven kidney or liver injury, along samples derived from critically ill patients to identify ferroptosis signatures in biofluids. We are developing immuno-based bead arrays to detect ferroptosis and factors released by dying cells, as well as (epi)sequencing cell free DNA in biofluids using Nanopore technology to detect tissue specific cell death. Precision medicine using innovative molecular diagnostics will bring intensive care into the 21st century.
Ferroptosis is increasingly recognized as a promising treatment option for cancer therapy. However, epigenetic changes have been reported as one of the mechanisms for anti-tumor drug resistance. The aim of this project is to understand how the epigenetic modifications affect ferroptosis resistance and how to revert them. In addition, diagnostic tools that predict tumor’s sensitivity for ferroptosis are still lacking. Therefore, we are also developing a Nanopore-seq based epi-ferroptosis biomarker assay (‘nFERROCATCH’) to systematically predict the sensitivity to ferroptosis-based cancer therapies.
Arterial media calcification (AMC) in the arterial wall is a major contributor to cardiovascular morbidity/mortality. This lethal, common disease has no effective therapy and is associated with high costs. Vascular smooth muscle cells play an important role in AMC as they transdifferentiate into bone-forming cells or undergo cell death under oxidative stress. We hypothesize that ferroptosis is detrimental factor because of the observed iron accumulation and lipid peroxidation in AMC. This project will further substantiate this role by (i) studying the AMC-inducing role of iron and (ii) genetically inducing lipid peroxidation in vascular smooth muscle cells. We then have the unique opportunity to investigate to what extent our lead ferroptosis inhibitor can slow down the development of AMC.
In the last 30 years, a worldwide increase in chronic kidney disease was reported in agricultural regions and hence was named Chronic Interstitial Nephritis in Agricultural Communities (CINAC). The exact cause and molecular disease mechanism underlying CINAC remain unknown. However, increasing evidence points towards exposure to agrochemicals (e.g. pesticides) as a causal factor. Recently, in kidney biopsies from CINAC-patients, we discovered a lysosomal lesion in proximal tubular cells (PTCs). Moreover, we discovered the same lesion in transplant patients treated with nephrotoxic immunosuppressive calcineurin inhibitors (CNIs), leading to the paradigm that CINAC indeed is caused by a toxin. We hypothesize that ferroptosis might play a role in this renal deterioration. Yet, the nature of the toxin, as well as cell biological mechanisms involved remain elusive. Therefore, we will focus our investigation on human renal biopsies of CINAC- and transplant-patients
Acute kidney injury (AKI) commonly caused by hampered blood flow, toxins and drugs, has far-reaching health consequences with >13.3 million patients each year. When AKI is not lethal, functional recovery usually occurs spontaneously. However, AKI also leads to chronic kidney disease (CKD) due to inefficiencies during spontaneous recovery. To date, there are no treatments that directly heal the injured kidney. Yet, the intriguing biological phenomenon of “nephrectomy-induced renal recovery” provides a new perspective. In this phenomenon an acutely injured kidney shows a remarkable recovery and averts progression to CKD when the healthy contralateral kidney is removed. Recent observations allowed to hypothesize that (ferroptotic) cell death might be crucial to obtain efficient kidney regeneration. Hence, this project aims for profound mechanistic and functional insight in these unexplored processes as they may foster new therapeutic designs. Hereto, we make use of state-of-the-art single cell transcriptomics as well as unique transgenic mouse models to investigate the cell death vs repair conundrum.
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