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1. WO2022162164 - METHODS OF ASSESSING THE RISK OF DEVELOPING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN PATIENTS TREATED WITH VLA-4 ANTAGONISTS

Publication Number WO/2022/162164
Publication Date 04.08.2022
International Application No. PCT/EP2022/052085
International Filing Date 28.01.2022
IPC
C12Q 1/6883 2018.1
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1Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6883for diseases caused by alterations of genetic material
C12Q 1/689 2018.1
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1Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6888for detection or identification of organisms
689for bacteria
CPC
C12Q 1/6883
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6883for diseases caused by alterations of genetic material
C12Q 1/689
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS
1Measuring or testing processes involving enzymes, nucleic acids or microorganisms
68involving nucleic acids
6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
6888for detection or identification of organisms
689for bacteria
C12Q 2600/106
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12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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2600Oligonucleotides characterized by their use
106Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
C12Q 2600/172
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12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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2600Oligonucleotides characterized by their use
172Haplotypes
Applicants
  • INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) [FR]/[FR]
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) [FR]/[FR]
  • CENTRE HOSPITALIER UNIVERSITAIRE DE TOULOUSE [FR]/[FR]
  • UNIVERSITÉ TOULOUSE III – PAUL SABATIER [FR]/[FR]
Inventors
  • AMAR, Jacques
  • BRASSAT, David
  • PIGNOLET, Béatrice
Agents
  • INSERM TRANSFERT
Priority Data
21305115.429.01.2021EP
Publication Language English (en)
Filing Language English (EN)
Designated States
Title
(EN) METHODS OF ASSESSING THE RISK OF DEVELOPING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN PATIENTS TREATED WITH VLA-4 ANTAGONISTS
(FR) PROCEDES D'ÉVALUATION DU RISQUE DE DÉVELOPPEMENT D'UNE LEUCO-ENTÉPHALOPATHIE MULTIFOCALE PROGRESSIVE CHEZ LES PATIENTS TRAITÉS PAR DES ANTAGONISTES DE LA VLA-4
Abstract
(EN) Natalizumab a monoclonal antibody is associated with the risk of progressive multifocal leukoencephalopathy (PML), an infection caused by the John Cunningham (JC) virus. The inventors explored the hypothesis that bacteria should be involved in the onset of PML in connection to the HLA-DR haplotype in multiple sclerosis (MS) patients. Thus 625 MS patients starting Natalizumab therapy from the BIONAT study were followed prospectively. Among those patients, 12 developed a PML. Outside the BIONAT cohort, we included nine additional MS patients with PML who had been referred to our center. For each patient, blood metagenomics sequencing and sequencing-based typing for HLA-DRB1*15:01 ancestral haplotype were determined. HLA-DRB1*15:01 haplotype carriers show a protection against PML (p=0.03). Among blood taxa, at genus level, Phyllobacterium was only significantly associated in HLA-DRB1*15:01 haplotype carriers with an inflammatory marker (p<0.0001) as opposed to HLA-DRB1*15:01 haplotype negative where no significant correlation was observed. Among the patients with no HLA-DRB1*15:01 haplotype, we showed a positive association (p=0.02) between the abundance of Phyllobacterium and PML whereas no significant association was observed in patients with HLA-DRB1*15:01 haplotype. JC positive virus patients with no HLA-DRB1*15:01 haplotype and a level of Phylobacterium in blood >2% have an odds ratio of 4.55 (95% confidence intervals 1.82-11.37; p=0.001) of developing or having PML under NTZ treatment. In conclusion, the inventors showed a relation between the HLA-DRB1*15:01 haplotype, the circulating microbiota and the risk of PML. The interaction between blood microbiota and the HLA-DRB1*15:01 haplotype may play a role in the virulence of the viruses.
(FR) Le Natalizumab (NTZ), un anticorps monoclonal, est associé au risque de leuco-encéphalopathie multifocale progressive (LEMP), une infection causée par le virus John Cunningham (JC). Les inventeurs ont exploré l'hypothèse voulant que des bactéries soient impliquées dans l'apparition de la LEMP en relation avec l'haplotype HLA-DR chez les patients atteints de sclérose en plaques (SEP). Ainsi, 625 patients atteints de SEP commençant un traitement par NTZ de l'étude BIONAT ont été suivis de manière prospective. Parmi ces patients, 12 ont développé une LEMP. En dehors de la cohorte BIONAT, nous avons inclus neuf autres patients atteints de SEP et atteints de LEMP ayant été adressés à notre centre. Pour chaque patient, le séquençage métagénomique du sang et le typage basé sur le séquençage pour l'haplotype ancestral HLA-DRB1*15:01 ont été déterminés. Les porteurs de l'haplotype HLA-DRB1*15:01 présentent une protection contre la PML (p=0,03). Parmi les taxons sanguins, au niveau du genre, Phyllobacterium était seulement associé de manière significative chez les porteurs de l'haplotype HLA-DRB1*15:01 à un marqueur inflammatoire (p<0,0001) par opposition aux porteurs de l'haplotype HLA-DRB1*15:01 négatifs où aucune corrélation significative n'a été observée. Parmi les patients sans haplotype HLA-DRB1*15:01, nous avons constaté une association positive (p=0.02) entre l'abondance de Phyllobacterium et la LEMP alors qu'aucune association significative n'a été observée chez les patients avec un haplotype HLA-DRB1*15:01. Les patients porteurs du virus JC positif sans haplotype HLA-DRB1*15:01 et avec un taux de Phylobacterium dans le sang >2% ont un odds ratio de 4,55 (intervalles de confiance à 95% 1,82-11,37 ; p=0,001) de développer ou d'avoir une LEMP sous traitement par NTZ. En conclusion, les inventeurs ont démontré une relation entre l'haplotype HLA-DRB1*15:01, le microbiote circulant et le risque de LEMP. L'interaction entre le microbiote sanguin et l'haplotype HLA-DRB1*15:01 pourrait jouer un rôle dans la virulence des virus.
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