Abstract
Haematopoietic stem cells in umbilical cord blood are an attractive target for gene therapy of inborn errors of metabolism. Three neonates with severe combined immunodeficiency were treated by retroviral–mediated transduction of the CD34+ cells from their umbilical cord blood with a normal human adenosine deaminase complementary DNA followed by autologous transplantation. The continued presence and expression of the introduced gene in leukocytes from bone marrow and peripheral blood for 18 months demonstrates that umbilical cord blood cells may be genetically modified with retroviral vectors and engrafted in neonates for gene therapy.
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References
Giblett, E.R., Anderson, J.E., Cohen, F., Pollara, B. & Meuwissen, H.J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2, 1067–1069 (1972).
Hershfield, M.S. & Mitchell, B.S. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 1725–1768 (McGraw-Hill, New York, 1994).
Parkman, R., Gelfand, E.W., Rosen, F.S., Sanderson, A. & Hirschhorn, R. Severe combined immunodeficiency and adenosine deaminase. New Engl. J. Med. 292, 714–719 (1975).
Weinberg, K.I. & Kohn, D.B. Somatic gene therapy for severe combined immunodeficiency (SCID). in Somatic Gene Therapy (ed. Chang, P.) 31–47 (CRC Press, Boca Raton, 1995).
Blaese, R.M. Development of gene therapy for immunodeficiency: adenosine deaminase deficiency. Pediatr. Res. 33 (suppl.), S49–S55 (1993).
Hershfield, M.S., Chaffee, S. & Sorensen, R.U. Enzyme replacement therapy with PEG-ADA in adenosine deaminase deficiency: Overview and case report of three patients, including two now receiving gene therapy. Pediatr. Res. 33 (suppl.), S42–S48 (1993).
Broxmeyer, H.E., Cooper, S., Yoder, M. & Hangoc, G. Human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells. Curr. Topics Microbiol. Immunol. 177, 195–204 (1992).
Wagner, J.E. et al. Transplantation of umbilical cord blood after myeloablative therapy: Analysis of engraftment. Blood 79, 1874–1881 (1992).
Hock, R.A., Miller, A.D. & Osborne, W.R. Expression of human adenosine deaminase from various strong promoters after gene transfer into human hematopoietic cell lines. Blood 74, 876–881 (1989).
Williams, D.A., Lemischka, I.R., Nathan, D.G. & Mulligan, R.C. Introduction of new genetic material into pluripotent haematopoietic stem cells of the mouse. Nature 310, 476–480 (1984).
Jordan, C.T. & Lemischka, I.R. Clonal and systemic analysis of long-term hematopoiesis in the mouse. Genes Dev. 4, 220–232 (1990).
Triglia, T., Peterson, M.G. & Kemp, D.J. A procedure for in vitro amplification of DNA segments that lie outside the boundaries of known sequences. Nucleic Adds Res. 16, 8186 (1988).
Ochman, H., Gerber, A.S. & Hartl, D.L. Genetic applications of an inverse polymerase chain reaction. Genetics 120, 621–623 (1988).
Rill, D.R. et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 84, 380–383 (1994).
Harrison, D.E. Competitive repopulation in unirradiated normal recipients. Blood 81, 2473–2474 (1993).
Stewart, F.M., Crittenden, R.B., Lowry, P.A., Pearson-White, S. & Quesenberry, P.J. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood 81, 2566–2571 (1993).
Wu, D.D. & Keating, A. Hematopoietic stem cells engraft in untreated transplant recipients. Expl. Hematol. 21, 251–256 (1993).
Van Beusechem, V.W., Kakler, A., Meidt, P.J. & Valerio, D. Long-term expression of human adenosine deaminase in rhesus monkeys transplanted with retrovirus-infected bone marrow cells. Proc. natn. Acad. Sci. U.S.A. 79, 7640–7644 (1992).
Bodine, D.M. et al. Long-term in vivo expression of a murine adenosine deaminase gene in rhesus monkey hematopoietic cells of multiple lineages after retroviral mediated gene transfer into CD34+ bone marrow cells. Blood 82, 1975–1980 (1993).
Brenner, M.K. et al. Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients. Lancet 342, 1134–1137(1993).
Valera, A., Perales, J.C., Hatzoglou, M. & Bosch, F. Expression of the neomycin-resistance (neo) gene induces alterations in gene expression and metabolism. Hum. Gene Ther. 5, 449–456 (1994).
Von Melchner, H. & Housman, D.E. The expression of neomycin phospho-transferase in human promyelocytic leukemia cells (HL-60) delays their differentiation. Oncogene 2, 137–140 (1988).
Miller, A.D. & Buttimore, C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Molec. cell. Biol. 6, 2895–2902 (1986).
Bassin, R.H., Tuttle, N. & Fischinger, P.J. Isolation of murine sarcoma virus-transformed mouse cells which are negative for leukemia virus from agar suspension cultures. Int. J. Cancer 6, 95–107 (1970).
Hanley, M.E., Nolta, J.A., Parkman, R. & Kohn, D.B. Umbilical cord blood cell transduction by retroviral vectors: Pre-clinical studies to optimize gene transfer. Blood Cells 20, 539–546 (1994).
Hershfield, M.S. et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modifled adenosine deaminase. New Engl. J. Med. 316, 589–596 (1987).
Nolta, J.A. & Kohn, D.B. Comparison of the effects of growth factors on retroviral vector-mediated gene transfer and the proliferative status of human hematopoietic progenitor cells. Hum. Gene Ther. 1, 257–268 (1990).
Nolta, J.A., Yu, X.J., Bahner, I. & Kohn, D.B. Retroviral mediated transfer of the human glucocerebrosidase gene into cultured Gaucher bone marrow. J. clin. Invest. 90, 343–348 (1992).
Weinberg, K. & Parkman, R. Severe combined immunodeficiency due to a specific defect in the production of interleukin-2. New Engl. J. Med. 322, 1718–1723 (1990).
Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyante-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).
Arredondo-Vega, F.X. et al. Paradoxical expression of adenosine deaminase in T cell cultured from a patient with adenosine deaminase deficiency and combined immunodeficiency. J. clin. Invest. 86, 444–452 (1990).
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Kohn, D., Weinberg, K., Nolta, J. et al. Engraftment of gene–modified umbilical cord blood cells in neonates with adenosine deaminase deficiency. Nat Med 1, 1017–1023 (1995). https://doi.org/10.1038/nm1095-1017
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DOI: https://doi.org/10.1038/nm1095-1017
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