Chemistry: molecular biology and microbiology – Virus or bacteriophage – except for viral vector or...
Patent
1996-04-12
1998-08-04
Campell, Bruce R.
Chemistry: molecular biology and microbiology
Virus or bacteriophage, except for viral vector or...
435 691, 4351723, 435236, 4353201, 514 2, 514 44, 935 22, 935 52, 935 55, C12N 700, C12N 704, C12N 1500, A61K 4800
Patent
active
057892300
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to the introduction of nucleic acids into higher eukaryotic cells.
DESCRIPTION OF RELATED ART
In recent years the therapeutic use of gene therapy for treating numerous diseases has aroused interest. Gene therapy is used to synthesise in vivo therapeutically active gene products, by means of which, e.g. in the case of a genetic defect, the function of the defective gene is replaced. Examples of genetically caused diseases in which gene therapy constitutes a promising approach are haemophilia, beta-thalassaemia and "Severe Combined Immune Deficiency" (SCID), a syndrome caused by a genetically induced deficiency of the enzyme adenosine deaminase. Other possible uses are in immune regulation, in which humoral or intracellular immunity is achieved by means of vaccination. Other examples of genetic defects in which a nucleic acid coding for the defective gene can be administered, for example, in a form which is individually tailored to the particular requirements, include muscular dystrophy (dystrophine gene), cystic fibrosis ("Cystic fibrosis transmembrane conductance regulator gene") and hypercholesterolaemia (LDL receptor gene). Gene-therapeutic treatment methods may also be used in order to synthesise hormones, growth factors or proteins with a cytotoxic or immunomodulating activity in the body.
Gene therapy is also a promising approach to the treatment of cancer, involving the administration of so-called cancer vaccines. In order to increase the immunogenicity of tumour cells, these cells are altered either to make them more antigenic or to cause them to produce certain immunomodulating substances, e.g. cytokines which then trigger an immune response. In order to bring this about, the cells are transfected with DNA which codes for a cytokine, e.g. IL-2, IL-4, IFN-gamma or TNF-.alpha.. The most developed techniques for gene transfer into autologous tumour cells make use of viral vectors.
Nucleic acids as therapeutically active substances are also used for inhibiting certain cell functions, e.g. antisense RNAs and -DNAs or ribozymes have proved to be effective agents for selectively inhibiting certain gene sequences.
In recent times, gene transfer systems have been developed which circumvent the restrictions of the retroviral and adenoviral vectors and exclude their safety risks which are based on the co-transfer of viable viral gene elements of the original virus. These gene transfer systems are based on mechanisms which the cell uses in order to transport macromolecules, e.g. by the extremely effective route of receptor-mediated endocytosis (Wu and Wu, 1987; EP-A1 0 388 758; WO 91/17773, WO 92/17210 and WO 92/19281). Using this method, which makes use of bifunctional molecular conjugates which have a DNA binding domain and a domain with specificity for a cell surface receptor, high gene transfer rates have been achieved.
Since gene transfer by physiological route, such as receptor mediated endocytosis using nucleic acid complexes, has major advantages (non-toxic mechanism of passage through the cell membrane; possibility of administration of biologically active nucleic acids on a repeated or continuous basis; possibility of cell-specific targeting; the ability to produce the conjugates in large amounts), there is a need to make this system more efficient.
When using gene transfer techniques based on the principle of receptor-mediated endocytosis, it became apparent that a limiting factor of the system is the breakdown of the genetic material in the cell after it has been released from the endosomes. A substantial improvement in the system was therefore achieved by a technique which exploits the ability of certain viruses and virus components to open up endosomes. By adding these endosomolytic agents a substantial increase was achieved in the expression rates of the genes imported into the cell (Wagner et al., 1991a and 1991b; Cotten et al., 1992; Wagner et al., 1992a and 1992b; Zatloukal et al., 1992; Cotten et al., 1993a and 1993b; Curiel et al. 1991; WO 93/
REFERENCES:
patent: 5635383 (1997-06-01), Wu et al.
Chiocca Susanna
Cotten Matthew
Schaffner Gotthold
Wagner Ernst
Boehringer Ingelheim International GmbH
Campell Bruce R.
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