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1. WO2020104467 - RECOMBINANT VECTORS SUITABLE FOR THE TREATMENT OF IPEX SYNDROME

Publication Number WO/2020/104467
Publication Date 28.05.2020
International Application No. PCT/EP2019/081820
International Filing Date 19.11.2019
IPC
C12N 15/86 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09Recombinant DNA-technology
63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
79Vectors or expression systems specially adapted for eukaryotic hosts
85for animal cells
86Viral vectors
CPC
C12N 15/86
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09Recombinant DNA-technology
63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
79Vectors or expression systems specially adapted for eukaryotic hosts
85for animal cells
86Viral vectors
Applicants
  • INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) [FR]/[FR]
  • UNIVERSITÉ PARIS DESCARTES [FR]/[FR]
  • ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP) [FR]/[FR]
  • FONDATION IMAGINE [FR]/[FR]
  • UNIVERSITÉ D’EVRY-VAL-D’ESSONNE [FR]/[FR]
  • ECOLE PRATIQUE DES HAUTES ETUDES [FR]/[FR]
  • MEDIZINISCHE HOCHSCHULE HANNOVER [DE]/[DE]
Inventors
  • ANDRE, Isabelle
  • SIX, Emmanuelle
  • BELLIER, Florence
  • DELVILLE, Marianne
  • CAVAZZANA, Marina
  • AMENDOLA, Mario
  • SCHAMBACH, Axel
Agents
  • INSERM TRANSFERT
Priority Data
18306526.720.11.2018EP
19305148.908.02.2019EP
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) RECOMBINANT VECTORS SUITABLE FOR THE TREATMENT OF IPEX SYNDROME
(FR) VECTEURS RECOMBINÉS APPROPRIÉS POUR LE TRAITEMENT DU SYNDROME IPEX
Abstract
(EN)
IPEX (Immune dysregulation Polyendocrinopathy X linked) syndrome is a primary immunodeficiency caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. Preclinical and clinical studies suggest that T cell gene therapy approaches designed to selectively restore the repertoire of Treg cells by transfer of wild type FOXP3 gene is a promising potential cure for IPEX. However, there is still a need for a vector that can be used efficiently for the preparation of said Treg cells. The inventors thus compared 6 different lentiviral constructs according to 4 criteria (vector titers, level of transduction of human CD4+ T cells, level of expression of FOXP3 and ΔLNGFR genes, degree of correlation between both expression) and selected one construct comprising a bidirectional PGK-EF1a promoter that showed remarkable efficiency.
(FR)
Le syndrome IPEX (syndrome de dérèglement immunitaire-polyendocrinopathie-entéropathie lié à l'X) est une immunodéficience primaire provoquée par des mutations dans le gène codant pour le facteur de transcription forkhead box p3 (FOXP3 ), conduisant à la perte fonctionnelle des lymphocytes T régulateurs CD4+ CD25+ issues du thymus (tTreg). Des études précliniques et cliniques suggèrent que des approches de thérapie génique à l'aide de lymphocytes T conçues pour restaurer sélectivement le répertoire de cellules Treg par transfert du gène FOXP3 de type sauvage est un remède potentiel prometteur pour l'IPEX. Cependant, il existe toujours un besoin pour un vecteur qui peut être utilisé efficacement pour la préparation desdites cellules Treg. Les inventeurs ont ainsi comparé 6 constructions lentivirales différentes selon 4 critères (titres vectoriels, niveau de transduction des lymphocytes T CD4+ humains, niveau d'expression des gènes FOXP3 et ΔLNGFR, degré de corrélation entre les deux expressions) et sélectionné une construction comprenant un promoteur PGK-EF1a bidirectionnel qui a montré une efficacité remarquable.
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