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.
Multiple organ dysfunction syndrome (MODS) is responsible for 30% of global deaths in intensive care units. Excess iron is a known contributor to cell death, specifically ferroptosis, and organ damage in critical illness. Collaborating with the Augustyns lab, we have developed, characterized, and patented novel ferroptosis inhibitors with improved efficacy, solubility, and stability. Among over 200 analogues, we identified three lead candidates with significantly enhanced solubility and stability compared to benchmark ferroptosis inhibitors. In numerous ferroptosis-driven experimental disease models, these lead candidates demonstrated strong in vivo protective effects. Remarkably, one of our lead candidates exhibited lifesaving efficacy against experimental multi-organ dysfunction, a feat unprecedented in the field. Launch of IRONIX, a ferroptosis therapeutic spin-off company, is planned in Q4 2024 to translate our ferroptosis-targeting drug candidates to clinic. For this, we are developing a companion diagnostic test to allow stratification of MODS patients.
The success of transplantation is hindered by a shortage of suitable organ grafts and the adverse effects of ischemia-reperfusion injury (IRI). Inflammation and cell death in the transplanted organ, triggered by the activation of the innate immune system during the IRI process, contribute to primary graft dysfunction (PGD). Transplant recipients experiencing severe PGD face heightened risks of early and late morbidity and mortality. To address these challenges, ex-vivo organ perfusion strategies have been developed to augment the pool of available grafts. During the ex-situ phase, which occurs between organ retrieval and transplantation, machine perfusion presents a unique opportunity for organ graft modulation to mitigate ferroptosis induced by IRI. Our in-house developed and patented lead ferroptosis inhibitor demonstrates superior efficacy in preclinical models of organ injury, positioning them as promising candidates for mitigating injury during transplantation.
In patients with sepsis or multi-organ failure syndrome (MODS), elevated plasma labile iron levels and excessive inflammasome signaling are recognized as critical factors associated with mortality. Excessive iron has been implicated in triggering ferroptosis and subsequent organ damage. Given the considerable variability observed in MODS and sepsis due to genetic variations, comorbidities, frailty, and dynamic disease courses, there is a pressing need for innovative biomarkers with predictive value to stratify clinically similar patients into distinct subtypes.
To address this heterogeneity, we employ genetic models of ferroptosis-induced kidney, liver or brain injury alongside samples obtained from critically ill patients to identify ferroptosis signatures in biofluids. Our approach involves the development of immuno-based bead arrays for the detection of ferroptosis and factors released by dying cells. Additionally, we utilize (epi)sequencing of cell-free DNA in biofluids using Nanopore technology to discern tissue-specific cell death patterns, and antimicrobial resistance.
The integration of precision medicine with innovative molecular diagnostics holds the potential to usher intensive care practices into the 21st century, allowing for more targeted and personalized therapeutic interventions.
Multiple sclerosis (MS) is an autoimmune disorder characterized by central nervous system inflammation and demyelination, propelled by an auto-amplifying cascade of inflammation and cell death. Analysis of MS lesions and cerebrospinal fluid from affected individuals has revealed several indicators of ferroptosis, including heightened levels of labile iron, peroxidized phospholipids, and lipid degradation products. Treatment with our leading ferroptosis inhibitor significantly delays relapses and mitigates disease progression in a preclinical model of relapsing-remitting MS.
Stroke, a devastating neurological condition, stands as a primary cause of disability and mortality worldwide. Despite its global health significance, effective acute therapies remain elusive. Emerging evidence suggests that ferroptosis may also play a role in stroke pathogenesis. Therefore, the objective of this research initiative is to explore the therapeutic potential of novel lead ferroptosis inhibitors capable of penetrating the blood-brain barrier in stroke-induced brain injuries. This pursuit holds promise for the development of innovative treatment modalities targeting this particular type of organ damage.
Neuroblastoma represents the most prevalent solid tumor found outside the brain among infants and very young children. The aggressive variant, known as high-risk neuroblastoma, is characterized by a dismal clinical prognosis, resistance to therapy, and a propensity for relapse. Addressing this challenge necessitates the exploration of novel molecular mechanisms to combat cancer cells.
Recently, we have uncovered a promising strategy for targeting aggressive, therapy-resistant neuroblastoma in mouse models by inducing a form of cellular deterioration known as ferroptosis. This approach exploits a process akin to biological rusting within cancer cells. Our ongoing efforts focus on developing innovative pharmacological and nanomedicinal interventions to enhance the therapeutic efficacy of ferroptosis in the treatment of neuroblastoma.
Ferroptosis is increasingly recognized as a promising avenue for cancer therapy. However, epigenetic changes have been identified as a mechanism underlying resistance to anti-tumor drugs. This project aims to elucidate how epigenetic modifications influence resistance to ferroptosis and explore strategies for reversing these alterations using epigenetic compounds derived from plants.
Furthermore, the lack of diagnostic tools to predict a tumor's sensitivity to ferroptosis poses a significant challenge. To address this gap, we are developing a novel Nanopore-sequencing-based assay, termed 'nFERROCATCH', designed to systematically assess tumor sensitivity to ferroptosis-based cancer therapies. This assay holds promise for enhancing our understanding of ferroptosis resistance mechanisms and facilitating the development of more effective cancer treatment strategies.
Metabolic syndrome can induce ectopic fat deposition in the liver, resulting in metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, there are no approved pharmacotherapies for MASLD, prompting exploration of novel treatment options targeting cell death-mediated injury. Given the observed lipotoxicity and iron dysregulation in non-alcoholic steatohepatitis (NASH), we hypothesized a potential involvement of ferroptosis in its pathogenesis.
Hepatic ferroptosis was identified in a subset of MASLD patients. Notably, ferroptosis defense mechanisms other than glutathione peroxidase 4 (GPX4) become prominent in MASLD livers. Pharmacological inhibition of ferroptosis attenuated MASLD progression in two mouse models. Therefore, targeting ferroptosis holds promise as a therapeutic strategy for MASLD.
Arterial media calcification (AMC) within the arterial wall significantly contributes to cardiovascular morbidity and mortality. This prevalent and lethal condition lacks effective therapeutic interventions and imposes substantial economic burdens. Vascular smooth muscle cells (VSMCs) play a pivotal role in AMC pathogenesis as they either transdifferentiate into bone-forming cells or undergo cell death in response to oxidative stress.
We hypothesize that ferroptosis is a contributing factor in AMC progression, given the observed accumulation of iron and lipid peroxidation. This project aims to substantiate this hypothesis by (i) investigating the role of iron in inducing AMC and (ii) genetically inducing lipid peroxidation in VSMCs. Subsequently, we will explore the efficacy of our leading ferroptosis inhibitor in mitigating AMC development, offering a unique opportunity to unravel the role of ferroptosis in this pathological process.
In the past three decades, there has been a global increase in chronic kidney disease, particularly in agricultural regions, leading to the designation of Chronic Interstitial Nephritis in Agricultural Communities (CINAC). The precise cause and molecular mechanisms underlying CINAC remain elusive. However, mounting evidence implicates exposure to agrochemicals, such as pesticides, as a potential causal factor.
Recently, in kidney biopsies obtained from patients with CINAC, we identified lysosomal lesions in proximal tubular cells (PTCs). Intriguingly, similar lesions were also observed in transplant patients treated with nephrotoxic immunosuppressive calcineurin inhibitors (CNIs), suggesting a common toxic etiology for CINAC. We hypothesize that ferroptosis may contribute to the renal deterioration observed in these cases. However, the identity of the toxin and the underlying cell biological mechanisms remain unclear.
To address these questions, our investigation will focus on analyzing human renal biopsies from both CINAC patients and transplant recipients. By examining these samples, we aim to elucidate the role of ferroptosis and uncover the mechanisms involved in the pathogenesis of CINAC.
Acute kidney injury (AKI), commonly triggered by compromised blood flow, toxins, and drugs, poses significant health risks, affecting over 13.3 million patients annually. While some cases of AKI resolve spontaneously without fatality, others lead to chronic kidney disease (CKD) due to inadequate recovery processes.
Currently, no treatments directly target kidney injury repair. However, the intriguing phenomenon of "nephrectomy-induced renal recovery" offers a novel perspective. This phenomenon involves the remarkable recovery of an acutely injured kidney and the prevention of CKD progression following removal of the healthy contralateral kidney.
Recent observations suggest that (ferroptotic) cell death may play a pivotal role in facilitating efficient kidney regeneration. As such, this project aims to gain comprehensive mechanistic and functional insights into these unexplored processes, with the potential to inform the development of innovative therapeutic approaches. To achieve this, we employ single-cell transcriptomics and utilize unique transgenic mouse models to investigate the interplay between cell death and repair mechanisms.
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