Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-08-15
1999-08-31
Degen, Nancy
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 514 14, 514 15, 530300, 530326, 530327, 530328, A61K 3810, A61K 3808, C07K 900, C07K 700
Patent
active
059454008
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the field of gene therapy and relates more particularly to the in vitro, ex vivo and/or in vivo transfer of genetic material. The invention proposes in particular a novel pharmaceutical composition which is useful for efficiently transfecting cells. The invention also relates to the uses of this composition.
Chromosomal deficiencies and/or anomalies (mutation, aberrant expression, and the like) are the cause of many diseases, of hereditary or non-hereditary nature. Conventional medicine has for a long time remained powerless as far as they are concerned. Nowadays, with the development of gene therapy, it is hoped to be able from now on to prevent or correct this type of chromosomal aberration. This novel medication consists in introducing genetic information into the affected cell or organ, for the purpose of correcting this deficiency or anomaly therein or alternatively for the purpose of expressing a protein of therapeutic value therein.
The main obstacle to the penetration of a nucleic acid into a cell or target organ lies in its size and the polyanionic nature of this nucleic acid, which oppose its passage across cell membranes.
In order to relieve this difficulty, various techniques are nowadays proposed including, more particularly, the transfection of naked DNA across the plasma membrane in vivo (WO90/11092) and the transfection of DNA via a transfection vector.
As regards the transfection of naked DNA, the efficacy of this still remains very low. Naked nucleic acids possess a short half-life in plasma on account of their degradation by enzymes and their removal via urinary routes.
Regarding the second technique, this also proposes two strategies:
The first uses natural transfection vectors, namely viruses. It is thus proposed to use adenoviruses, herpes-viruses, retroviruses and, more recently, adeno-associated viruses. Although these vectors prove to be of high performance as regards transfection, it is unfortunately not possible to exclude as far as they are concerned certain risks of pathogenicity, replication and/or immunogenicity, which are inherent to their viral nature.
The second strategy consists advantageously in using non-viral agents capable of promoting the transfer and expression of DNA in eukaryotic cells.
The subject of the present invention is directed more particularly towards this second strategy.
Chemical or biochemical vectors represent an advantageous alternative to natural viruses, in particular for this absence of viral recombination and/or immunological response. They have no pathogenic power, there is no risk of multiplication of the DNA within these vectors and there is no theoretical limit associated therewith as regards the size of the DNA to be transfected.
These synthetic vectors have two main functions, to condense the DNA to be transfected and to promote its cell binding as well as its passage across the plasma membrane and, where appropriate, the two nuclear membranes.
On account of its polyanionic nature, DNA naturally has no affinity for the plasma membrane of cells, which membrane is also polyanionic. In order to overcome this drawback, non-viral vectors generally all have polycationic charges.
Among the synthetic vectors developed, cationic polymers of polylysine and DEAE dextran type or alternatively cationic lipids or lipofectants are the most advantageous. They have the property of condensing DNA and of promoting its association with the cell membrane. More recently, the concept of targeted transfection mediated by a receptor has been developed. This technique exploits the principle of condensing DNA, by virtue of the cationic polymer, while at the same time directing the binding of the complex to the membrane using a chemical coupling between the cationic polymer and the ligand of a membrane receptor present at the surface of the cell type which it is desired to graft. Screenings of the receptor with transferring and insulin, and screening of the hepatocyte asialoglycoprotein receptor have thus been described.
However, the syn
REFERENCES:
patent: 5354844 (1994-10-01), Beug et al.
Orkin et al. Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy, Dec. 1995.
Dubes et al., Rapid Ephemeral Cell Sensitization as the Mechanism of Histone-Induced and Protamine-Induced Enhancement of Transfection by Poliovirus RNA, Protoplasma, vol. 96, pp. 209-223 (Jan. 1, 1978).
Wienhues et al., A Novel Method for Transfection and Expression of Reconstituted DNA-Protein Complexes in Eukaryotic Cells, DNA, vol. 6, No. 1, pp. 81-89 (Feb. 1, 1987).
Bottger et al., Condensation of vector DNA by the chromosomal protein HMG1 results in efficient transfection, Biochimica et Biophysica Acta, vol. 950, No. 2, pp. 221-228 (Jul. 13, 1988).
Cornetta et al., Protamine sulfate as an effective alternative to polybrene in retroviral-mediated gene-transfer: implications for human gene therapy, J.Virol.Methods, vol. 23, No. 2, pp. 187-194 (Feb. 1, 1989).
Byk Gerardo
Scherman Daniel
Schwartz Bertrand
Degen Nancy
Hansen Christine M.
Parker III Raymond S.
Rhone-Poulenc Rorer SA
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