Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Molecular bilayer structure
Patent
1997-02-28
2000-01-11
Houtteman, Scott W.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Molecular bilayer structure
435 6, 514 44, A61K 9127
Patent
active
06013240&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compositions based on nucleic acids, to their preparation and to their use. More especially, it relates to compositions comprising at least one nucleic acid and some cationic polymers, and to their use for the transfer of nucleic acids into cells, in particular in gene therapy.
Gene therapy consists in correcting a deficiency or an abnormality (mutation, aberrant expression, and the like) or in effecting the expression of a protein of therapeutic value by introducing genetic information into the affected cell or organ. This genetic information may 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. Different techniques have been described for transferring this genetic information, including 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) and of DNA and polylysine, 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 gene transfer has been seen to be a promising alternative to these physicochemical transfection techniques. In this connection, different viruses have been tested for their capacity to infect certain cell populations. In particular, retroviruses (RSV, HMS, MMS, and the like), the HSV virus, adeno-associated viruses and adenoviruses may be mentioned.
However, the techniques developed hitherto do not enable the difficulties associated with gene transfer into cells and/or the body to be resolved satisfactorily. In particular, the problems associated with the entry of nucleic acid into cells are not completely solved. In effect, the polyanionic nature of nucleic acids, in particular, prevents their passage through cell membranes. While it has been shown that naked nucleic acids are capable of passing through the plasma membrane of some cell types in vivo (see, in particular, Application No. WO90/11092), the efficiency of transfection remains rather low. Furthermore, naked nucleic acids have a short plasma half-life on account of their degradation by enzymes and their elimination in the urine. Moreover, while recombinant viruses enable the efficiency of transfer of nucleic acids to be improved, their use presents some risks, such as pathogenicity, transmission, replication, recombination, transformation, immunogenicity, and the like. Furthermore, their production according to the specifications of Good Manufacturing Practice presents some difficulties.
The present invention provides an advantageous solution to these different problems. The Applicant has, in effect, shown that some cationic polymers possess especially advantageous properties for the transfer of nucleic acid into cells, both in vitro and in vivo. In addition, these polymers have the advantage of being readily accessible and inexpensive. The use of cationic polymers according to the invention also enables the drawbacks associated with the use of viral vectors (potential dangers, limited size of the gene transferred, higher cost, and the like), to be avoided.
More especially, the present invention lies in the demonstration of the transfecting properties of the polymers of formula (I): ##STR1## in which R can be a hydrogen atom or a group of formula ##STR2## n is an integer between 2 and 10; p and q are integers, on the understanding that the sum p+q is such that the average molecular weight of the polymer is between 100 and 10.sup.7 Da.
It is understood that, in the formula (I), the value of n can vary between the different units p. Thus, the formula (I) embraces both homopolymers and heteropolymers.
A first subject of the invention is therefore a composition comprising at least one nucleic acid and a cationic polymer of general formula (I) as defined above.
The invention also relates to the use of the cationic pol
Behr Jean-Paul
Boussif Otmane
Demeneix Barbara
Lezoualch Franck
Mergny Mojgan
Houtteman Scott W.
Parker III Raymond S.
Rhone-Poulenc Rorer SA
Savitzky Martin F.
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