Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Patent
1994-12-01
1999-03-30
Robinson, Douglas W.
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
4351723, 4353201, C12N 1500, C12N 1563
Patent
active
058888209
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF INVENTION
Recent advances in autologous bone marrow transplant strategies indicate that normal hematopoiesis can be promptly restored in patients treated with myelotoxic agents (drugs or radiation) by re-injection of autologous peripheral blood (CD34.sup.+) "stem cells" (Gianni, et al., Lancet 2:580, 1989). In addition, it has very recently been reported that CD34.sup.+ cells can be transduced in vitro at high efficiency with retroviral vectors expressing specific genes (Bregni, et al., Blood 80:1418, 1992). These technologies open the way to approaches in which the in vitro transduction of specific genes into autologous CD34.sup.+ cells followed by reinoculation into patients can be used to transduce genes of therapeutic significance. This gene therapy approach includes the reconstitution of drug-resistant hematopoietic cells allowing for subsequent treatment with higher dose myelotoxic chemotherapy in cancer patients.
SUMMARY OF INVENTION
This invention provides a vector which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase.
In addition, this invention provides a vector which comprises a nucleic acid molecule encoding a human glutamylcysteine synthetase.
In addition, this invention provides a retroviral vector, which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase.
In addition, this invention provides a retroviral vector, which comprises a nucleic acid molecule encoding a human glutamylcysteine synthetase.
In addition, this invention provides a vector, which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase and a glutamylcysteine synthetase.
In addition, this invention provides a method for reducing the toxic effects of a cyclophosphamide in a subject which comprises replacing the subject's hematopoietic cells with hematopoietic cells of having the retroviral vector which comprises a nucleic acid molecule encoding a human cytosolic aldehyde dehydrogenase so as to reduce the toxic effects of the cyclophosphamide in the subject.
In addition, this invention provides a method for introducing a selectable marker into a mammalian cell which comprises transfecting the cell with a nucleic acid molecule encoding human cytosolic aldehyde dehydrogenase.
In addition, this invention provides a method for selecting mammalian cells expressing a protein of interest which comprises: a) introducing into the cells a nucleic acid molecule comprising a nucleic acid molecule encoding the protein of interest and the nucleic acid molecule encoding human cytosolic aldehyde dehydrogenase; b) culturing the resulting transfected cells; and c) selecting cells which express human cytosolic aldehyde dehydrogenase, so as to obtain cells which express the protein of interest.
In addition, this invention provides a method for reducing the toxic effects of a cyclophosphamide in a subject which comprises replacing the subject's hematopoietic cells with hematopoietic cells of having the retroviral vector which comprises a nucleic acid molecule encoding a human glutamylcysteine synthetase so as to reduce the toxic effects of the cyclophosphamide in the subject.
In addition, this invention provides a method for introducing a selectable marker into a mammalian cell which comprises transfecting the cell with a nucleic acid molecule encoding human glutamylcysteine synthetase.
In addition, this invention provides a method for selecting mammalian cells expressing a protein of interest which comprises: a) introducing into the cells a nucleic acid molecule comprising a nucleic acid molecule encoding the protein of interest and the nucleic acid molecule encoding human glutamylcysteine synthetase; b) culturing the resulting transfected cells; and c) selecting cells which express human glutamylcysteine synthetase, so as to obtain cells which express the protein of interest.
In addition, this invention provides an isolated mammalian nucleic acid molecule encoding a cytosolic aldehyde dehydrogenase. The isolated mammalian nucleic ac
REFERENCES:
Narahanan et al. Deveopment of an amphotropic, high-titer retrovirus vector expressing the dihydrofolate reductase gene and conferring methotrexate resistance, Gene 48:71-80, 1986.
Russo et al. Characterization of cytosolic aldehyde dehydrogenase from cyclophosphamide resistant L1210 cells, Cancer Research 48:2963-2968, 1988.
Bregni, M., et al. (1992) "Human Peripheral Blood Hematopoietic Progenitors Are Optimal Targets Of Retroviral-Mediated Gene Transfer." Blood 80: 1418-1422.
Canellos, G.P., et al. (1970) "Combination Chemotherapy For Metastatic Breast Carcinoma." Cancer 38: 1882-1886 (Exhibit B).
Correll, P.H., et al. (1989) "Production of Human Glucocerebrosidase In Mice After Retroviral Gene Transfer Into Multipotential Hematopoietic Progenitor Cells." Proc. Natl. Acad. Sci. U.S.A. 86: 8912-8916 (Exhibit C).
Gianni, A.M., et al. (1989) "Granulocyte-Macrophage Colony-Stimulating Factor Two Harvest Circulating Haemopoietic Stem Cells For Autotransplantation." The Lancet 2: 580-585.
Hempel, J., et al., (1984) "Aldehyde Dehydrogenase From Human Liver." Eur. J. BioChem. 141: 21-35.
Hsu, L.C., et al. (1989) "Genomic Structure Of The Human Cytosolic Aldehyde Dehydrogenase Gene." Genomics 5: 857-865.
Hsu, L.C., et al. (1985) "Cloning of cDNAs For Human Alhehyde Dehydrogenases 1 And 2." Proc. Natl. Acad. Sci. U.S.A. 82: 3771-3775.
Mann, R., et al. (1983) "Construction Of A Retrovirus Packaging Mutant And Its Use To Produce Helper-Free Defective Retrovirus." Cell 33: 153-159.
Miller, A.D. and C. Buttmore (1986) "Redesign Of Retrovirus Packaging Cell Lines To Avoid Recombination Leading To Helper Virus Production." Molecular and Cellular Biology 6: 2895-2902.
Miller, A.D. and G.J. Rosman (1989) "Improved Retroviral Vectors For Gene Transfer And Expression." BioTechniques 7: 980-990.
Siena, S., et al. (1989) "Circulation of CD34 Hematopoietic Stem Cells In The Peripheral Blood of High-Dose Cyclophosphamide-Treated Patients: Enhancement By Intravenous Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor." Blood 74: 1905-1914.
Dalla-Favera Riccardo
Gianni Alessandro Massimo
Robinson Douglas W.
The Trustees of Columbia University in the City of New York
Wai Thanda
White John P.
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