Genetic Therapy Using Bone Marrow Transplantation
Genetic therapy often involves the use of replication-incompetent retroviral vectors that are designed to carry information into the genome of the somatic cells of the body. The strategies most frequently utilized have involved the ex vivo modification of hematopoietic cells, as shown in Table 1 [1–9]. These strategies have involved the harvesting of peripheral blood and marrow early progenitor cells, following which these cells are incubated ex vivo with the transducing vector and then reinfused into the patients after delivery of some form of preparative therapy that is designed to reduce the number of competing cells. In those cases in which correction of the genetic defect in the hematopoietic cells has provided a selective growth advantage to the hematopoietic cells, there has been no necessity for the use of preparative therapy to ensure the dominance of the genetically modified cells following transplantation. In addition, because the frequency of the genetic modification is often in the 2–10% range for retroviral vectors, and often the genetic modification confers no selective advantage on the modified cells, several investigators have initiated in vitro animal models and in vivo clinical trials in humans that are designed to test if chemotherapy resistance genes can be used to confer a selective growth advantage on the genetically modified cells to ensure that the modified cells will be retained after transduction and transplantation.
KeywordsHematopoietic Cell Acute Myelogenous Leukemia Autologous Bone Marrow Transcription Unit Familial Hypercholesterolemia
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- 4.Rill DR, Buschle M, Foreman NK, Bartholomew C, Moen RC, Santana VM, Inle JN, Brenner MK: Retro virus mediated gene transfer as an approach to analyze neuroblastoma relapse after autologous bone marrow transplantation. Human Gene Ther 3:129–136,1992.Google Scholar
- 6.Claxton D, Suh S-P, Eilaccio M, Ellerson D, Gaozza E, Andersson B, Brenner M, Reading C, Feinberg A, Moen R, Belmont J, Moore K, Talpaz M, Kantarjian H, Deisseroth A: Molecular analysis of retro viral transduction in chronic myelogenous leukemia. Human Gene Ther 2:317–321, 1991.CrossRefGoogle Scholar
- 7.Etkin M, Filaccio M, Ellerson D, Suh S-P, Claxton D, Gaozza E, Brenner M, Moen R, Belmont J, Moore KA, Moseley AM, Reading C, Khouri I, Talpaz M, Kantarjian H, Deisseroth A: Use of cell-free retro viral vector preparations for transduction of cells from the marrow of chronic phase and blast crisis chronic myelogenous leukemia patients and from normal individuals. Human Gene Ther 3:137–145, 1992.CrossRefGoogle Scholar
- 12.Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF, Hester J, Korbling M, Durett A, Moen R, Berenson R, Heimfeld S, Brenner M, Hamer J, Calvert L, Tibbits P, Talpaz M, Kantarjian H, Champlin R, Reading C: Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia contribute to relapse after autologous bone marrow in CML. Blood 83:3068–3076, 1994.PubMedGoogle Scholar
- 13.Kasid A, Morechi S, Aebersold P, Cornetta K, Culver K, Freeman S, Director E, Lotze MT, Blaese RM, Anderson WF, Rosenbetrg S: Human gene transfer: Characterization of human tumor infiltrating lymphocytes as vehicles for retroviral mediated gene transfer in man. Proc Natl Acad Sci USA 87:473–477, 1990.PubMedCrossRefGoogle Scholar
- 14.Wilson J, personal communication, 1994.Google Scholar
- 17.Hanania EG, Fu S, Zu Z, Hegewisch-Becker S, Korbling M, Andreeff M, Mechetner E, Roninson I, Giles R, Berenson R, Heimfeld S, Deisseroth AB: Chemotherapy resistance to taxol in clonogenic progenitor cells following transduction of CD34 selected marrow and peripheral blood cells with a retro virus that contains the MDR-1 chemotherapy resistance gene. Gene Ther, In Press, 1995.Google Scholar
- 18.Hanania EG, Fu S, Roninson I, Zu Z, Gottesman MM, Deisseroth AB: Resistance to taxol chemotherapy produced in mouse marrow cells by safety-modified retroviruses containing a human MDR-1 transcription unit. Gene Ther, In Press, 1995.Google Scholar
- 20.Kantarjian H, Talpaz M, Hester J, Korbling M, Liang J, Rios MB, Calvert L, Deisseroth AB: Collection of peripheral blood diploid cells from chronic myelogenous leukemia patients early in the recovery phase from myelosuppression induced by conventional dose chemotherapy. J Clin Oncol 13:553–559, 1995.PubMedGoogle Scholar