Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1995-10-11
1998-12-01
Low, Christopher S. F.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
424 9321, 435325, 4353201, 4351723, 435 691, A61K 4800
Patent
active
058434321
DESCRIPTION:
BRIEF SUMMARY
This application claims priority on and is the National Stage application of PCT International Application No. PCT/FR93/01259 filed on 16 Dec. 1993.
Gene therapy offers novel possibilities for the treatment of tumors.
Among the difference options, the objective of gene transfer is to kill the tumor cells either indirectly by the induction or the reinforcement of an immune response of the host (S. A. Rosenberg, Cancer Res. 51: 5074(1991) or directly by the insertion of a "suicide gene" (F. L. Moolten, Cancer Res. 46: 52-76 (1986)). The most studied suicide gene is that coding for thymidine kinase of type 1 herpes simplex virus (TK-HSV1) (G. B. Elion et al., J. Antimicrob. Chemother. 12: 9-17 (1983)). This enzyme phosphorylates nucleoside analogues such as ganciclovir (GCV). The monophosphate molecules are then converted into the triphosphate forms by cellular enzymes. The GCV triphosphate (GCV-TP) can then be incorporated into the DNA during cell division, blocking elongation and thus leading to the death of the cell. GCV-TP is thus only toxic for dividing cells.
This approach is particularly interesting for the treatment of tumors which are constituted of rapidly dividing cells in a tissue constituted of non-proliferating cells, and the expression of TK-HSV1 by the cells of a tumor situated within an organ whose cells are not dividing ought to permit the specific destruction of these cells. Furthermore, it is possible to target gene transfer into these tumor cells by using for the transduction of TK-HSV1 recombinant retroviruses whose genome can only be integrated and expressed in dividing cells.
The first experimental ablation model by GCV of tumor cells expressing TK-HSV1 was set up by Moolten (F. L. MOOLTEN, Cancer Res., 46, 1986, p. 5276-5281); F. L. MOOLTEN and J. M. WELLS, J. Natl. Cancer Inst., 82, 1990, p. 297-300). He showed an antitumor effect of GCV on the growth of tumor cells in mice after transfection of the TK-HSV1 gene in vitro, and reimplantation in the animal. Recently, the elimination of microscopic experimental cerebral tumors by stereotaxic injection of cells producing TK-HSV1 retroviruses and treatment by GCV has been reported by Culver (K. W. Culver et al., Science 256: 1550-1552 (1992)).
However, in this model the authors were unable to analze the effect of such a treatment on macroscopic established tumors which rapidly become lethal. Now, in patients solid tumors are the principal target of this type of treatment and the problem of the transduction of the suicide genese in the context of a tumoral mass is much more problematical.
In man, hepatic metastases are a frequent complication of digestive cancers. Partial hepatectomy is only possible in about 15% of cases, and other treatments such as local chemotherapy or immunotherapy have hitherto given only modest, even disappointing results. The present work shows the efficacy of the treatment of experimental hepatic metastases in the rat after in vivo transfer of the TK-HSV1 gene by direct injection of murine fibroblasts producing recombinant retroviral particles.
In this context, one of the objectives of the present invention is the development of a packaging cell-recombinant retroviral vector system utilizable in therapy to treat established tumors, in particular hepatic tumors, and in which the expression product of the recombinant gene is capable of converting a non-toxic prodrug into a drug toxic for the cells expressing said recombinant gene.
More precisely, the objective of the present invention is to construct a recombinant retroviral vector capable, after transformation of a fibroblast packaging line, of producing retroviral pseudoparticles which, after infection of dividing cells, results in the expression of the transduced gene without leading to inactivation of said vectors which occurs and has been described in particular with MuLV-Moloney.
The murine transgenic lines of the Mov series were established by Jaenisch et al. by infection of mouse embryos with the Moloney-MuLV virus before implantation (Jaenisch et al., Cell
REFERENCES:
patent: 5529774 (1996-06-01), Barba et al.
Ledley, F.D. Clinicla considerations in the design of protocols for somatic gene therapy. Human Gene Therapy 2:77-83, 1991.
Plautz, G. et al. Selective eliminatin of recombinant genes in vivo with a suicide retroviral vector. New Biologist 3:709-715, 1991.
Caruso et al., Proc. Natl. Acad. Sci. USA, 90, pp. 7024-7028 (1993).
Culver et al., Science, 256, No. 5063, pp. 1550-1551 (1992).
Mastrangelo et al., Seminalr in Oncology, vol. 23, 1: 4-21 1996.
Jain, Scientific Amercian, vol. 27, No:1 pp. 58-65, 1994.
Gunzburg et al., Molecular Medicine Today, vol.1 No.9, pp. 410-417, 1995.
Crystal, Science, vol. 270, pp. 404-410, 1995.
Connors, Gene Therapy, 2, 10: 702-709, 1995.
Girboa, Seminars in Oncology, 23, 1: pp. 101-107, 1996.
Deonamain et al., Gene Therapy, 2: 235-244, 1995.
Barklis et al., Cell 47:391-399 (1986).
Jaenisch et al., Cell 24:519-529 (1981).
Caruso Manuel
Klatzmann David
Low Christopher S. F.
Nguyen Dave Trong
Universite Pierre Et Marie Curie (Paris VI)
LandOfFree
Retroviral vectors for the treatment of tumors, and cell lines c does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Retroviral vectors for the treatment of tumors, and cell lines c, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Retroviral vectors for the treatment of tumors, and cell lines c will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2393315