Recombinant adenoviruses for gene therapy in cancers

Details Recombinant adenoviruses for gene therapy in cancers Recombinant adenoviruses for gene therapy in cancers

1996-05-13

1998-11-17

Low, Christopher S. F.

Plastic article or earthenware shaping or treating: apparatus

Means to form preform from bulk and means to convolute or...

Convoluting means includes an endless surface

4361723, 436 691, 436 914, 436325, 514 44, C12N 1563

Patent

active

058375317

DESCRIPTION:

BRIEF SUMMARY
This application is a national phase application under 35 U.S.C. 371 of PCT/FR 94/01284, filed Nov. 07, 1994.
The present invention relates to recombinant vectors of viral origin and to their use for the treatment of cancers. More particularly, it relates to recombinant adenoviruses containing a heterologous DNA sequence under the control of expression signals which are active specifically in tumour cells. The invention also relates to the preparation of these vectors, to the pharmaceutical compositions containing them and to their use in gene therapy.
Gene therapy consists in correcting a deficiency or an abnormality (mutation, aberrant expression and the like) by the introduction of a genetic information into the cell or the affected organ. This genetic information can be introduced either in vitro into a cell extracted from the organ, the modified cell then being reintroduced into the body, or directly in vivo into the appropriate tissue. Various techniques have been described for the introduction of this genetic information, amongst which are various transfection techniques involving complexes of DNA and DEAE-dextran (Pagano et al., J. Virol. 1 (1967) 891), of DNA and nuclear proteins (Kaneda et al., Science 243 (1989) 375), of DNA and lipids (Felgner et al., PNAS 84 (1987) 7413), the use of liposomes (Fraley et al., J. Biol. Chem. 255 (1980) 10431), and the like. More recently, the use of viruses as vectors for the transfer of genes appeared as a promising alternative to these physical transfection techniques. In this respect, various viruses have been tested for their capacity to infect certain cell populations, in particular retroviruses (RSV, HMS, MMS and the like), HSV virus, adeno-associated viruses, and adenoviruses.
Numerous applications of gene therapy are under study, such as genetic diseases (myopathy, cystic fibrosis, SCID, and the like), pathologies of the central nervous system (Alzheimer, Parkinson, and the like), cardiovascular diseases (haemophilia, atherosclerosis), AIDS or cancers. More particularly, as regards the treatment of cancers, various strategies have been proposed in-the prior art. Thus, Application EP 259 212 describes the preparation of vaccines intended for the treatment of cancers, comprising a modified virus capable of expressing an antigen specific for a tumour, permitting an immune response to be generated against these cells. Moreover, Application WO91/15580 describes the construction of retroviruses containing a gene encoding a ribozyme, whose expression in cell culture can make it possible to destroy an mRNA of an oncogene. It is also known from Application WO93/10814 to use vectors expressing immunogenic, non-tumorigenic forms of cellular oncogenes involved in the development of cancers. Application WO93/02556 finally describes the use of cells removed from the tumour, which are genetically modified ex vivo by the introduction of a toxic gene, then readministered to the patient. However, this approach requires surgical steps, and furthermore, the stability of the toxic gene in the cell transformed ex vivo is not established.
Consequently, although valuable results have been obtained, the constructs described in the prior art do not make it possible to satisfactorily solve some difficulties, and especially the precise screening of the cells to be treated. Thus, it has been proposed to use recombinant retroviruses as vectors for the transfer of therapeutic genes. Indeed, these viruses are capable of infecting only the cells which divide. However, the use of this type of vector does not make it possible to screen, with sufficient selectivity, the tumour cells. Furthermore, these viruses cannot be obtained at very high titres, thereby limiting the therapeutic efficacy. It has moreover been proposed to directly administer the gene into the tumour. Here again, the risks of diffusion to the surrounding cells are not excluded. For this reason, it has been proposed to modify the host specificity of the viruses used, by incorporating into their envelopes proteins recognizi

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