Julie Foucquier

Pharnext (France)

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Daniel Cohen

Plant & Food Research

Mickaël Guedj

Servier (France)

Laurent Sandrin

Ipsen (France)

Nathalie Cholet

Pharnext (France)

Nathalie Perrot

Université Paris-Saclay

Véronique Miette

École Nationale Vétérinaire d'Alfort

Rodolphe Hajj

Pharnext (France)

Serguei Nabirotchkin

Pharnext (France)

Céline Fournier‐Poizat

Ipsen (France)

Sébastien Gaucel

Food Process Engineering and Microbiology

Cooperative Institutions

European Foundation for the Study of Chronic Liver Failure

Inserm

Pharnext (France)

Centre National de la Recherche Scientifique

Sorbonne Université

National Yang Ming Chiao Tung University

University of North Carolina at Chapel Hill

Virginia Commonwealth University

UNSW Sydney

Assistance Publique – Hôpitaux de Paris

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[P3–047]: A COMBINATION OF ACAMPROSATE AND BACLOFEN (PXT864) SYNERGIZES WITH STANDARDS OF CARE FOR THE TREATMENT OF ALZHEIMER's DISEASE

Alzheimer s & Dementia (2017)

Nathalie Cholet Julie Foucquier Niall Murphy Mickaël Guedj Serguei Nabirotchkin

Enhancing the efficacy of drugs targeting cognitive decline in Alzheimer disease (AD), together with improving their safety, has been a long-term goal of therapeutic development. Currently approved standards of care (SOCs) exhibit transient efficacy and their use is accompanied by undesirable side effects. Thus, drug combination therapies, particularly those applying low doses, may represent next generation therapies for AD. We previously demonstrated the synergistic effectiveness of a combination therapy (known as PXT864) consisting of two repurposed drugs – acamprosate and baclofen – in AD models. As patients are usually treated with a SOC, we investigated whether the efficacy of these SOCs at inactive doses is improved by combining them with low or inactive doses of PXT864. To this end, we assessed the efficacy of PXT864 combined with the SOCs, donepezil or memantine, on different cellular and behavioral endpoints in an in vitro neuronal primary culture model intoxicated with oligomeric β-amyloid peptides (Aβ), and an in vivo intracebroventricular Aβ-injection mouse model. We found that tri-therapy with PXT864+donepezil or PXT864+memantine synergistically protected neuronal cells against Aβ toxicity with a higher protective effect than the individual drugs alone. In AD model animals, doses of individual drugs selected for their inactivity, and binary combinations of such doses of individual drugs, were totally ineffective whereas the tri-therapeutic combination synergistically alleviated cognitive deficits. These findings highlight the value of using repurposed drugs combined with low doses of existing SOC therapeutics, and emphasize the value of network pharmacology approach that allows to discover combinations with new mechanisms of action.

Memantine

Baclofen

Acamprosate

Combination therapy

10.1016/j.jalz.2017.06.1860

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Combinational Drug Repurposing from Genetic Networks Applied to Alzheimer’s Disease

Journal of Alzheimer s Disease (2022)

Serguei Nabirotchkin Jan Bouaziz Fabrice Glibert Jonas Mandel Julie Foucquier

Background: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. Objective: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. Methods: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. Results: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. Conclusion: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer’s disease.

Drug repositioning

Repurposing

Drug Development

Genome-wide Association Study

10.3233/jad-220120

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A Rasch Analysis of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) in a Cohort of Charcot-Marie-Tooth Type 1A Patients

PLoS ONE (2017)

Wenjia Wang Mickaël Guedj Viviane Bertrand Julie Foucquier Élisabeth Jouve

The Charcot-Marie-Tooth Neuropathy Score (CMTNS) was developed as a main efficacy endpoint for application in clinical trials of Charcot-Marie-Tooth disease type 1A (CMT1A). However, the sensitivity of the CMTNS for measuring disease severity and progression in CMT1A patients has been questioned. Here, we applied a Rasch analysis in a French cohort of patients to evaluate the psychometrical properties of the CMTNS. Overall, our analysis supports the validity of the CMTNS for application to CMT1A patients though with some limitations such as certain items of the CMTNS being more suitable for moderate to severe forms of the disease, and some items being disordered. We suggest that additional items and/or categories be considered to better assess mild-to-moderate patients.

Tooth disease

10.1371/journal.pone.0169878

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Citations (14)

Contents

Journal of Hepatology (2023)

Patrizia Burra Felix Tacke Vlad Ratziu S Zeuzem Bruno Sangro

10.1016/s0168-8278(22)03380-3

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Guided-VCTE: An Enhanced FibroScan Examination With Improved Guidance and Applicability

Ultrasound in Medicine & Biology (2025)

Cécile Bastard Stéphane Audière Julie Foucquier Hugo Lorée Véronique Miette

Although FibroScan (FS), based on Vibration-Controlled Transient Elastography (VCTE), is a widely used non-invasive device for assessing liver fibrosis and steatosis, its current standard-VCTE examination remains timely and difficult on patients with obesity. The Guided-VCTE examination uses continuous shear waves to locate the liver by providing a real-time predictive indicator for shear wave propagation and uses shear wave maps averaging to increase the signal-to-noise ratio in difficult to assess patients. We aimed to evaluate the effectiveness of the new indicator, as well as compare examination times and success rates with both standard-VCTE and Guided-VCTE examinations. We recruited 130 patients all with varying BMI in this multicenter study. Sensitivity, specificity, positive predictive values and negative predictive values assessed the new indicator effectiveness. Success rates were compared using Wilcoxon signed rank tests rates and time-to-event analyses were used to investigate examination times. Agreement and repeatability of both methods were assessed using Wilcoxon signed-rank test. The new indicator was highly effective, with a 97% sensitivity for predicting valid liver stiffness measurements (LSM). LSM and controlled attenuation parameter results remained in good agreement between two examinations. The Guided-VCTE examination significantly increased the success rate of individual measurements and significantly reduced the time required for localization in the study cohort, especially in patients with grade 2 obesity (BMI ≥35 kg/m²). Additionally, the proportion of patients scanned in less than 4 minutes was significantly higher with the Guided-VCTE examination. Guided-VCTE is a new effective technique that simplifies further FS use, particularly for patients with obesity.

10.1016/j.ultrasmedbio.2024.12.007

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Modelling the formation of the lipid droplet interface and networks during an emulsion of a milk gel.

HAL (Le Centre pour la Communication Scientifique Directe) (2012)

Julie Foucquier Sébastien Gaucel Claire Surel Alain Riaublanc Marc Anton

Interface (matter)

Source

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Analysis of drug combinations: current methodological landscape

Pharmacology Research & Perspectives (2015)

Julie Foucquier Mickaël Guedj

Abstract Combination therapies exploit the chances for better efficacy, decreased toxicity, and reduced development of drug resistance and owing to these advantages, have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need. In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest. Research in this field has resulted in a large number of papers and revealed several issues. Here, we propose an overview of the current methodological landscape concerning the study of combination effects. First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect‐based approaches and dose–effect‐based approaches, and introduced in light of their respective practical advantages and limitations. Then, we discuss six main common methodological issues that scientists have to face at each step of the development of new combination therapies. In particular, in the absence of a reference methodology suitable for all biomedical situations, the analysis of drug combinations should benefit from a collective, appropriate, and rigorous application of the concepts and methods reviewed here.

10.1002/prp2.149

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Citations (944)

Treatment monitoring with the Agile 3+ score in patients with non-alcoholic steatohepatitis: analysis of data from a randomised placebo-controlled trial of semaglutide

Journal of Hepatology (2023)

Laurent Castéra Céline Fournier‐Poizat Julie Foucquier Mette Mandrup Kjær Niels Krarup

Steatohepatitis

Semaglutide

10.1016/s0168-8278(23)02279-1

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Citations (1)

Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy

Orphanet Journal of Rare Diseases (2014)

Ilya Chumakov Aude Milet Nathalie Cholet Gwenaël Primas Aurélie Boucard

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models. We thus hypothesized that a polytherapeutic approach using several drugs, previously approved for other diseases, could be beneficial by simultaneously targeting PMP22 and pathways important for myelination and axonal integrity. A combination of drugs for CMT1A polytherapy was chosen from a group of authorised drugs for unrelated diseases using a systems biology approach, followed by pharmacological safety considerations. Testing and proof of synergism of these drugs were performed in a co-culture model of DRG neurons and Schwann cells derived from a Pmp22 transgenic rat model of CMT1A. Their ability to lower Pmp22 mRNA in Schwann cells relative to house-keeping genes or to a second myelin transcript (Mpz) was assessed in a clonal cell line expressing these genes. Finally in vivo efficacy of the combination was tested in two models: CMT1A transgenic rats, and mice that recover from a nerve crush injury, a model to assess neuroprotection and regeneration. Combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol, termed PXT3003, improved myelination in the Pmp22 transgenic co-culture cellular model, and moderately down-regulated Pmp22 mRNA expression in Schwannoma cells. In both in vitro systems, the combination of drugs was revealed to possess synergistic effects, which provided the rationale for in vivo clinical testing of rodent models. In Pmp22 transgenic CMT1A rats, PXT3003 down-regulated the Pmp22 to Mpz mRNA ratio, improved myelination of small fibres, increased nerve conduction and ameliorated the clinical phenotype. PXT3003 also improved axonal regeneration and remyelination in the murine nerve crush model. Based on these observations in preclinical models, a clinical trial of PTX3003 in CMT1A, a neglected orphan disease, is warranted. If the efficacy of PTX3003 is confirmed, rational polytherapy based on novel combinations of existing non-toxic drugs with pleiotropic effects may represent a promising approach for rapid drug development.

Schwann cell

Nerve Injury

10.1186/s13023-014-0201-x

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Citations (86)

Modelling the formation of fat droplet interface during homogenisation in order to describe the texture

Procedia Food Science (2011)

Julie Foucquier Sébastien Gaucel Claire Surel Alain Riaublanc Cédric Baudrit

Abstract The homogenisation is an important operation in the dairy product processes, characterised by disruption of fat globules and then, coalescence between fat droplets and adsorption of milk proteins (monomers, polymers and aggregates of proteins) and other surfactants on fat droplet surface. Moreover, the homogenisation has often an impact on the textural properties of the products. In the literature, there are some articles dealing with the modelling of the phenomena occurring during the homogenisation. The aim of this work is to express some properties of the texture of the product from the structure. However, the models existing in the literature characterise the structure at a too fine scale to be linked to the texture. Consequently, we attempt to implement a mathematical model able to describe the interface of fat droplets during homogenisation at a mesoscopic scale involving texture. The approach consists in coupling models for the formation of the interface of fat droplets with an expert model to obtain the texture of the product, leading to an integrated knowledge model. This paper focuses on the model of formation of interface of fat droplets, using a mechanistic approach built from literature, expert knowledge and measurements and the qualitative is performed. Afterwards, an expert model, non deterministic, will be built with the output of the mechanistic model and the expert knowledge.

Coalescence (physics)

Globules of fat

Mesoscopic physics

Interface (matter)

Texture (cosmology)

10.1016/j.profoo.2011.09.107

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Citations (2)