gilbert bensimon | Sorbonne University (original) (raw)
Papers by gilbert bensimon
PubMed, Jul 2, 2002
Within the framework of an early drug access programme launched in 1995, a multicentre open study... more Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.
Brain Communications
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor ... more Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cyc...
Science Translational Medicine
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated herita... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation–based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol...
Supplementary Figures S1-S5, Supplementary Methods. (DOCX 8021 kb)
Neurology, 2017
Objective: To evaluate the safety and activity of low dose Interleukin-2 (ld IL-2) in Amyotrophic... more Objective: To evaluate the safety and activity of low dose Interleukin-2 (ld IL-2) in Amyotrophic Lateral Sclerosis (ALS). Background: Blood regulatory T-cells (Tregs) level is a strong predictor of ALS disease severity. In auto-immune/auto-inflammatory conditions, ld IL-2 was reported to safely expand Tregs, inducing significant clinical improvements. Design/Methods: This was a double-blind, placebo-controlled, randomized (12 patients/group), parallel-group study of ld IL-2 (1MIU and 2 MIU/days s.c.) for 5 days every 4 weeks for 3 cycles. Assessment times were: before each cycle, 3 days after cycle 1 & 3 (T e max), 3 weeks after 3 rd cycle, and 3 months after last dosing. Primary criteria: Tregs at T e max/cycle-1 (expressed as numbers: Tregn and as % of CD4: Treg%). Secondary criteria: Tregs at all other study times, immuno-inflammatory blood-cells, cytokines/chemokines, functional decline (ALSFRS, Vital Capacity), and neurofilaments (NFs) levels. Safety was assessed from randomiz...
Movement Disorders, 2019
Approach to Alzheimer's Disease). All SNP genotyping was performed at the Neuroscience Genomics C... more Approach to Alzheimer's Disease). All SNP genotyping was performed at the Neuroscience Genomics Core at UCLA and funded by a generous gift from the Chen Family Foundation (to J.M.B.). UCLA genetics investigators (D.G., G.C., J.L., J.A.C.) were sponsored by the Tau Consortium and the Chen Family Foundation. Z.C. was supported by funding from the National Institute for Health Research (NIHR) Academic Clinical Fellowship scheme.
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Magnetic resonance imaging (MRI) has the potential to aid characterise of disease progression in ... more Magnetic resonance imaging (MRI) has the potential to aid characterise of disease progression in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).MethodsSix patients with probable MSA (mean age (years±SD) was 61±10.4) and 7 with PSP (64.7±5.9 years) according to NNIPPS criteria were prospectively recruited for MRI scanning at King's College Hospital. Illness duration at baseline was 5.6±2 (MSA) and
EBioMedicine, 2020
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Distributed under a Creative Commons Attribution-NonCommercial-NoDerivatives| 4.0 International License
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for pert...
The Lancet. Neurology, 2018
Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a d... more Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole. In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research ...
The Lancet. Neurology, 2018
Nature communications, Mar 21, 2017
We have previously shown higher-than-expected rates of schizophrenia in relatives of patients wit... more We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel ...
Nature genetics, Sep 25, 2016
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated ... more To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Plos One 4 Article E7114, Sep 22, 2009
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkin... more Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035). We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. ClinicalTrials.gov NCT00211224.
Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control, 1995
PubMed, Jul 2, 2002
Within the framework of an early drug access programme launched in 1995, a multicentre open study... more Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.
Brain Communications
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor ... more Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cyc...
Science Translational Medicine
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated herita... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation–based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol...
Supplementary Figures S1-S5, Supplementary Methods. (DOCX 8021 kb)
Neurology, 2017
Objective: To evaluate the safety and activity of low dose Interleukin-2 (ld IL-2) in Amyotrophic... more Objective: To evaluate the safety and activity of low dose Interleukin-2 (ld IL-2) in Amyotrophic Lateral Sclerosis (ALS). Background: Blood regulatory T-cells (Tregs) level is a strong predictor of ALS disease severity. In auto-immune/auto-inflammatory conditions, ld IL-2 was reported to safely expand Tregs, inducing significant clinical improvements. Design/Methods: This was a double-blind, placebo-controlled, randomized (12 patients/group), parallel-group study of ld IL-2 (1MIU and 2 MIU/days s.c.) for 5 days every 4 weeks for 3 cycles. Assessment times were: before each cycle, 3 days after cycle 1 & 3 (T e max), 3 weeks after 3 rd cycle, and 3 months after last dosing. Primary criteria: Tregs at T e max/cycle-1 (expressed as numbers: Tregn and as % of CD4: Treg%). Secondary criteria: Tregs at all other study times, immuno-inflammatory blood-cells, cytokines/chemokines, functional decline (ALSFRS, Vital Capacity), and neurofilaments (NFs) levels. Safety was assessed from randomiz...
Movement Disorders, 2019
Approach to Alzheimer's Disease). All SNP genotyping was performed at the Neuroscience Genomics C... more Approach to Alzheimer's Disease). All SNP genotyping was performed at the Neuroscience Genomics Core at UCLA and funded by a generous gift from the Chen Family Foundation (to J.M.B.). UCLA genetics investigators (D.G., G.C., J.L., J.A.C.) were sponsored by the Tau Consortium and the Chen Family Foundation. Z.C. was supported by funding from the National Institute for Health Research (NIHR) Academic Clinical Fellowship scheme.
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Magnetic resonance imaging (MRI) has the potential to aid characterise of disease progression in ... more Magnetic resonance imaging (MRI) has the potential to aid characterise of disease progression in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).MethodsSix patients with probable MSA (mean age (years±SD) was 61±10.4) and 7 with PSP (64.7±5.9 years) according to NNIPPS criteria were prospectively recruited for MRI scanning at King's College Hospital. Illness duration at baseline was 5.6±2 (MSA) and
EBioMedicine, 2020
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Distributed under a Creative Commons Attribution-NonCommercial-NoDerivatives| 4.0 International License
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for pert...
The Lancet. Neurology, 2018
Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a d... more Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole. In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research ...
The Lancet. Neurology, 2018
Nature communications, Mar 21, 2017
We have previously shown higher-than-expected rates of schizophrenia in relatives of patients wit... more We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel ...
Nature genetics, Sep 25, 2016
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated ... more To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Plos One 4 Article E7114, Sep 22, 2009
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkin... more Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035). We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. ClinicalTrials.gov NCT00211224.
Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control, 1995