Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1996-01-19
1999-05-25
Campell, Bruce R.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
424 931, 424422, 424423, 435325, 435326, 435382, 435395, 435397, 435400, 6048911, 935 62, A01N 6300, A61K 4800
Patent
active
059068175
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a biocompatible implant for the expression of defined substances in man or in animals, in particular for the anchoring of the recombinant cells of the invention.
The present invention also relates to retroviral vectors for the preparation of recombinant cells capable of being implanted in vivo for a therapeutic purpose.
STATE OF THE ART
The in vivo introduction of implants capable of expressing defined substances for example for therapeutic purposes necessitates the use of efficacious agents as regards the desired therapeutic or prophylactic objective and that the organism into which the implant is introduced has the capacity to tolerate it in the relatively long-term.
The earlier international patent application published under the number 92/15676 described agents to obtain in vivo the expression of defined nucleotide sequences for the purpose of a therapeutic treatment of diseases resulting from a genetic anomaly. This international application 92/15676 proposes the use of fibroblasts genetically modified by a retroviral vector for the purpose of implanting them in the connective tissue of the skin of the subject to be treated.
The nucleotide sequence whose expression is desired in this earlier international application is placed under the control of the LTR (Long Terminal Repeat) sequence of the retroviral vector and/or under the control of inducible or constitutive exogenous promoters, the LTR sequence of the retrovirus being nonetheless conserved when the exogenous promoter is present.
SUMMARY OF THE INVENTION
The invention proposes agents making it possible to achieve in vivo the expression of a selected nucleotide sequence under conditions such that this expression is obtained over a period of several months, preferably more than 6 months, in a manner such that the product of the nucleotide sequence expressed is present in sufficient quantity and under conditions suitable for the production of a desired therapeutic effect in vivo.
The agents defined in the present application make it possible to achieve the expression and the secretion of a protein, glycoprotein or a peptide of biological interest to justify its therapeutic use in vivo.
The invention also relates to the use of biocompatible materials as supports for the introduction into man or animals of cells for example recombinant cells of the invention defined below, starting from which it is desired to produce a defined molecule in particular for therapeutic purposes.
The preparation of implants requires such supports suitable for being placed in contact with cells and various factors promoting the adhesion of these cells to the support if necessary, under conditions such that the different constituents present conserve their principal natural structural and functional properties.
These biocompatible supports whether of biological origin or not may or may not be resorbable by the host into which they are introduced.
The invention also concerns retroviral vectors having the capacity to infect cells, and in particular eukaryotic cells, as well as the recombinant cells including these vectors. The recombinant cells of the invention may be administered or implanted in a patient, thus producing in vivo a protein or any expression product of a defined nucleotide sequence inserted into the retroviral vector.
The inventors have examined which are the parameters which, at various levels, would make it possible to express in vivo a defined nucleotide sequence so as to improve the expression of the nucleotide sequence inserted in the vector in order to obtain a therapeutic effect, if necessary of long duration.
Thus, they have demonstrated that when the exogenous nucleotide sequence whose expression is desired is advantageously placed in the vector intended for the infection of the cells under the control of an inducible or constitutive exogenous promoter, the LTR sequence internal to the retroviral vector must then be partially deleted. The deletion must be sufficient to impair the transcription of the mRNA.
DETAILED DES
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Danos Olivier
Ferry Nicolas
Heard Jean-Michel
Moullier Philippe
Campell Bruce R.
Institut Pasteur
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