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Permanent epigenetic gene silencing

A technology for silencing, target genes, in the field of gene silencing and/or epigenetic editing

Active Publication Date: 2017-08-29
OSPEDALE SAN RAFFAELE SRL +1
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Problems solved by technology

However, these studies failed to demonstrate permanent epigenetic silencing in the absence of continuous expression of ATR, possibly due to the ability of selected effector domains to reestablish a self-propagating chromatin repression state at ATR target loci. Inner inability

Method used

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Embodiment 1

[0547] To recapitulate the endogenous epigenetic mechanism that permanently silences endogenous retroviruses (ERVs) during development, we employed the human zinc finger protein 10 (ZNF10; Szulc, J. et al. (2006) Nat. Methods3: 109-16) and the catalytic domain of human DNA methyltransferase 3A (DNMT3A; Law, J.A. et al. (2010) Nat. Rev. Genet. 11:204-20). The amino acid sequences of these domains are shown in Table 1.

[0548] To test the activity and stability of gene silencing induced by these two effector domains, we used a tetracycline (tet) responsive system. We fused the two effector domains to the Escherichia coli tetracycline-controlled repressor (tetR) DNA-binding domain (Gossen, M. et al. (1992) Proc. Natl. Acad. Sci. USA89:5547-51), generating tetR:KRAB and tetR:DNMT3A artificial transcriptional repressors (ATR, hereinafter referred to as tetR:K and tetR:D3A, respectively). An advantage of the tetR system is that it allows temporal control of the binding of tetR to...

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Abstract

A product comprising two or more artificial transcription repressors (ATRs), or polynucleotides encoding therefor, selected from groups (a), (b), (c) or (d): (a) an ATR comprising a DNA-binding domain operably linked to a KRAB domain or homologue thereof; (b) an ATR comprising a DNA-binding domain operably linked to a DNMT3A, DNMT3B or DNMT1 domain or homologue thereof; (c) an ATR comprising a DNA-binding domain operably linked to a DNMT3L domain or homologue thereof; and (d) an ATR comprising a DNA-binding domain operably linked to a SETDB1 domain or homologue thereof, wherein at least two of the ATRs are selected from different groups (a), (b), (c) or (d).

Description

field of invention [0001] The present invention relates to gene silencing and / or epigenetic editing. More specifically, the present invention relates to improved methods for silencing a gene of interest or for editing the epigenetic state of a genetic element of interest, including during gene therapy applications. Background of the invention [0002] Gene therapy involves incorporating genetic material into cells to treat or prevent disease. Genetic material can complement defective genes with functional copies of those genes, inactivate genes that are not functioning properly or introduce new therapeutic genes into cells. [0003] A classic example of gene therapy is gene replacement, in which a dysfunctional gene is replaced with a DNA sequence encoding a functional therapeutic gene (Naldini, L. (2011) Nat. Rev. Genet. 12:301-15; Kay, M.A. (2011) Nat .Rev.Genet.12:316-28; Biffi,A.et al.(2013)Science 341:1233158;Aiuti,A.etal.(2013)Science 341:1233151;Aiuti,A.et al.(2009)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/85A61K35/12A61K38/17A61K38/45A61K48/00
CPCA61K35/12A61K38/1709A61K38/45A61K48/005C12N9/1007C12N15/85C07K14/4703C12Y201/01037C12Y201/01043C07K2319/80C12N2740/16043A61K38/00C12N9/22C12N2310/20C12N15/113C12N2800/80
Inventor L.纳尔迪尼A.L.隆巴尔多A.阿马比尔A.米格利亚拉
Owner OSPEDALE SAN RAFFAELE SRL
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