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Targeted Nanocarriers For Targeted Drud Delivery Of Gene Therapeutics

A nano-carrier and drug technology, applied in the medical field, can solve problems that hinder the effectiveness of gene targeting

Inactive Publication Date: 2018-02-09
RODOS BIOTARGET
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Poor cellular uptake of therapeutic oligonucleotides hampers gene targeting effectiveness in vitro and in vivo

Method used

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  • Targeted Nanocarriers For Targeted Drud Delivery Of Gene Therapeutics
  • Targeted Nanocarriers For Targeted Drud Delivery Of Gene Therapeutics
  • Targeted Nanocarriers For Targeted Drud Delivery Of Gene Therapeutics

Examples

Experimental program
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example

[0076]In the case of HIV-1, the gene-therapy approach described herein is to inhibit the proliferation of the virus by (i) genome editing via plasmid-encoded TALEN activity, or (ii) via sense or antisense oligonucleotides. Nucleotides block selected viral genes. Infection by HIV-1 can be used as an example, since the viral genome will integrate into the host genome as a so-called HIV-1 provirus. The same method, or variants thereof, can be transferred or adapted to other indications.

[0077] A. Studies Using Plasmid DNA

example 1

[0078] Example 1: Targeted Lipid-Based Nanocarriers

[0079] According to the basic protocol previously published (Gieseler Rk et al., March 21, 2005, WO / 2005 / 092288; Gieseler Rk et al., Scand J Immunol [Scandinavian Immunology Journal] 2004;59:415- 24. PMID15140050) Formulation of nanocarriers. However, a modification was made to the protocol in that the density of the targeting anchors was increased to 8% of the surface density of the fucose-derived anchors used to localize cells via C-type lectin receptors expressed on the cell surface, or 8% of the surface density of galactose-derived anchors for targeting cells via asialoglycoprotein receptors expressed on the cell surface. In addition, liposome compositions can be modified using: phosphatidylcholine (PC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-di Oleoyl-sn-glyceryl-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), cholesteryl hemisuccinate (CHEMS), soybean phosphatidyl Choli...

example 2

[0080] Example 2: Encapsulation of plasmid DNA in nanocarriers

[0081] The DNA in the form of a plasmid (p-DNA) encapsulates the gene encoding green fluorescent protein (GFP) as a reporter gene or the sequence encoding TALEN. As a basis for previous protocols, encapsulation of DNA was performed initially (Pupo E et al J ContrRelease 2005;104:379-96; Bailey AL and Sullivan SM. Biochim BiophysActa 2000;1468:239-52). However, a modification was made to the protocol in that the formulation parameters of multilamellar vesicles (MLV) to produce small unilamellar vesicles (SUVs) were compared with the high pressure homogenization parameters (extrusion: 50 nm or 100 nm) Revise. Also, as a way to increase the packing ratio, speed mixing is introduced to ultimately leave an acceptable payload packing ratio. Unencapsulated DNA payloads were removed by dialysis from phosphate buffer in which nanocarriers were dissolved. However, omitting the dialysis step may be a future option, sinc...

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Abstract

The present invention relates to targeted nanocarriers - also termed nanomedicines - and methods of preferentially, or actively, targeting and delivering a tool for gene transfer or genome editing (i.e., a plasmid or a restriction enzyme - such as a zinc finger nuclease, a CRISPR / Cas system, or a TALEN) or a tool for gene silencing or post-transcriptional regulation of gene expression (i.e., a microRNA, a siRNA, a mRNA, an antisense oligonucleotide, or a sense oligonucleotide) to a range of mammalian cell species. Cell- specific targeting is achieved by using nanocarriers featuring suitable targeting anchors having a targeting moiety that can be a carbohydrate, an antibody or an antibody fragment, a non-antibody protein derivative, an aptamer, a lipoprotein or a fragment thereof, a peptidoglycan, a lipopolysaccharide or a fragment thereof, or a CpG DNA. Such targeting anchors may or may not include a polymeric spacer like polyethylene glycol. The nanomedicines shall allow to therapeutically address a range of mammalian disease entities via various application routes. These indications include malignant diseases, autoimmune diseases, inherited disorders, metabolic disorders, or infectious diseases.

Description

technical field [0001] The present invention relates to the field of medicine, and in particular to the targeted delivery of gene therapy agents via nanocarriers to mammalian cells affected by a range of disease entities that can be treated or cured by such therapeutic intervention. Background technique [0002] Targeted delivery of bioactive molecules to mammalian cells (such as cancer cells) remains challenging with many obstacles, especially in vivo. These hurdles include (a) the composition, functional characteristics, and stability of the delivery vehicle, (b) packaging of biologically active molecules in therapeutically significant concentrations, (c) targeting of desired diseased cells in vivo, (d) overcoming different cellular intracellular barrier and successfully deliver therapeutic concentrations of bioactive molecules to intracellular targets, (e) evade a range of components of the host immune system, such as antibodies, complement factors, and macrophages, that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127C12N15/11A61K38/46A61K48/00A61K47/69A61K47/61A61K47/54A61P37/02A61P3/00A61P31/00
CPCA61K9/127A61K38/465A61K48/005C12N15/111C12N2310/14C12N2310/16C12N2320/32C12N2310/20A61K38/00A61K47/549A61K47/61A61K47/6911A61K47/6913A61K31/7125A61P3/00A61P31/00A61P37/02
Inventor 马库斯·福尔克罗伯特·基泽勒
Owner RODOS BIOTARGET
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