H U M A N G E N E THERAPY 2:111-112 (1991) Mary Ann Liebert, Inc., Publishers
H I V
M E E T I N G PRESENTATION
Infection a n d G e n e T r a n s f e r T h e r a p y
DOUGLAS J. JOLLY
INTRODUCTION Gene TRANSFER has traditionally been considered a possible therapy for genetic diseases. While this is appropriate in a limited number of situations (e.g., adenosine deaminase deficiency), the real power of gene transfer is its ability to produce large protein and/or R N A molecules inside cells. In a sense it is a drug delivery system for such molecules. With this perspective, it is possible to imagine many ways of affecting disease progression in m a n y different diseases, including viral diseases or cancer (Baltimore, 1988). However, it is necessary to realize the limitations of current technology and propose procedures that are feasible scientifically, clinically, and in a regulatory sense.
that it should be used initially for life-threatening conditions, and again, initially, that treatment of cells should occur outside the patient to allow rigorous control of the procedure before returning the cells to the patient.
CTL INDUCTION
Such considerations have led us to develop a system to elicit cytotoxic T lymphocyte (CTL) responses using retroviral vectors (Barber et al., 1991; J. Warner et al., submitted). This system includes retroviral vector constructs, high-efficiency, safe packaging cell lines, scale-up of vector production, and in vitro culture and vector infection of cells. Resistance to or recovery from a number of diseases is thought to be linked to the generation of C T L (Townsend and McMichael, 1985). W e have used a mouse model to show that THERAPEUTIC TACTICS expression of H I V genes introduced by a retroviral vector leads to induction of powerful C T L responses in a highly reproducible Proposed therapeutic tactics include antisense (von Ruden and Gilboa, 1989) f raw-dominant viral repressors (Malim et fashion. These responses are conventional M H C class I real., 1989), and replacement of defective tumor suppressor genes stricted responses and are mediated by C D 8 + cells. The doses (Bookstein etal., 1990). These tactics and others have been used required are moderate (106-107 cells) and hence do not require a to cure or alleviate pathological effects in tissue culture. At large production effort. The cells administered are apparently Viagene, w e have also investigated an approach to human eliminated by the response they generate. immunodeficiency virus (HIV) therapy whereby a gene that responds to H I V infection is introduced into cells and produces CONCLUSION an enzyme that is capable of converting a prodrug into an active form (Barber et al., 1991). This was performed using a retroviral vector delivery system (Friedmann, 1989). This system involves The potential for such treatments to induce therapeutic CTL the introduction of an HIV-inducible H S V thymidine kinase responses in general, and, in particular, against H I V infection, gene into cells followed by treatment with Acyclovir or an seems promising. The therapy can be partially tested in large analogue. This is very effective in selectively killing H I V animal models but ultimately only human clinical trials will show h o w effective such an approach can be. infected cells at otherwise nontoxic drug levels. However, to use such approaches clinically, it is necessary to target particular cell types and introduce genes into a large REFERENCES number of cells which represent close to 1 0 0 % ofthe pathogenic population. In addition, gene expression often has to be wellcontrolled and continuous over periods of time measured in BALTIMORE, D. (1988). Gene therapy intracellular immunization. Nature 335, 395-396. years. While this will be possible in the future, use of gene transfer technology as it exists n o w has steered us toward B A R B E R , J.D., JOLLY, D.J., ST. LOUIS, D., and W A R N E R , J.F. (1991). Utilization of retroviral vectors for the potential treatment of approaches where no targeting is necessary, large numbers of AIDS. Annual Review of AIDS Research (in press). cells do not have to be treated and gene expression does not have BOOKSTEIN, R., S H E W , J-Y., C H E N , P-L., S C U L L Y , P., and LEE, to be tightly controlled or maintained for long periods of time. In W-H. (1990). Suppression of tumorigenicity of human prostate addition, the relatively untried nature ofthe technology suggests Viagene, Inc., San Diego, C A 92121.
Ill
112 carcinoma cells by replacing a mutated R B gene. Science 247, 712-715. F R I E D M A N N , T. (1989). Progress toward human gene therapy. Science 244, 1275-1281. M A L I M , M.H., B O H N L E I N , J.H., and C U L L E N , B.R. (1989). Functional dissection of the HIV-1 rev trans-activator—derivation of a trans-dominant repressor of rev function. Cell 58, 205-214. T O W N S E N D , A.R.M., and M c M I C H A E L , A.J. (1985). H L A class I restriction of T cell mediated cytotoxicity. Prog. Allergy 36, 110143.
JOLLY V O N RUDEN,T., and GILBOA, E. (1989). Inhibition of human T-cell leukemia virus type I replication in primary human T cells that express antisense R N A . J. Virol. 63, 677-682. Address reprint requests to: Dr. Douglas J. Jolly Viagene, Inc. 11075 Rose lie Street San Diego, C A 92121
H I V
M E E T I N G PRESENTATION
Infection a n d G e n e T r a n s f e r T h e r a p y
DOUGLAS J. JOLLY
INTRODUCTION Gene TRANSFER has traditionally been considered a possible therapy for genetic diseases. While this is appropriate in a limited number of situations (e.g., adenosine deaminase deficiency), the real power of gene transfer is its ability to produce large protein and/or R N A molecules inside cells. In a sense it is a drug delivery system for such molecules. With this perspective, it is possible to imagine many ways of affecting disease progression in m a n y different diseases, including viral diseases or cancer (Baltimore, 1988). However, it is necessary to realize the limitations of current technology and propose procedures that are feasible scientifically, clinically, and in a regulatory sense.
that it should be used initially for life-threatening conditions, and again, initially, that treatment of cells should occur outside the patient to allow rigorous control of the procedure before returning the cells to the patient.
CTL INDUCTION
Such considerations have led us to develop a system to elicit cytotoxic T lymphocyte (CTL) responses using retroviral vectors (Barber et al., 1991; J. Warner et al., submitted). This system includes retroviral vector constructs, high-efficiency, safe packaging cell lines, scale-up of vector production, and in vitro culture and vector infection of cells. Resistance to or recovery from a number of diseases is thought to be linked to the generation of C T L (Townsend and McMichael, 1985). W e have used a mouse model to show that THERAPEUTIC TACTICS expression of H I V genes introduced by a retroviral vector leads to induction of powerful C T L responses in a highly reproducible Proposed therapeutic tactics include antisense (von Ruden and Gilboa, 1989) f raw-dominant viral repressors (Malim et fashion. These responses are conventional M H C class I real., 1989), and replacement of defective tumor suppressor genes stricted responses and are mediated by C D 8 + cells. The doses (Bookstein etal., 1990). These tactics and others have been used required are moderate (106-107 cells) and hence do not require a to cure or alleviate pathological effects in tissue culture. At large production effort. The cells administered are apparently Viagene, w e have also investigated an approach to human eliminated by the response they generate. immunodeficiency virus (HIV) therapy whereby a gene that responds to H I V infection is introduced into cells and produces CONCLUSION an enzyme that is capable of converting a prodrug into an active form (Barber et al., 1991). This was performed using a retroviral vector delivery system (Friedmann, 1989). This system involves The potential for such treatments to induce therapeutic CTL the introduction of an HIV-inducible H S V thymidine kinase responses in general, and, in particular, against H I V infection, gene into cells followed by treatment with Acyclovir or an seems promising. The therapy can be partially tested in large analogue. This is very effective in selectively killing H I V animal models but ultimately only human clinical trials will show h o w effective such an approach can be. infected cells at otherwise nontoxic drug levels. However, to use such approaches clinically, it is necessary to target particular cell types and introduce genes into a large REFERENCES number of cells which represent close to 1 0 0 % ofthe pathogenic population. In addition, gene expression often has to be wellcontrolled and continuous over periods of time measured in BALTIMORE, D. (1988). Gene therapy intracellular immunization. Nature 335, 395-396. years. While this will be possible in the future, use of gene transfer technology as it exists n o w has steered us toward B A R B E R , J.D., JOLLY, D.J., ST. LOUIS, D., and W A R N E R , J.F. (1991). Utilization of retroviral vectors for the potential treatment of approaches where no targeting is necessary, large numbers of AIDS. Annual Review of AIDS Research (in press). cells do not have to be treated and gene expression does not have BOOKSTEIN, R., S H E W , J-Y., C H E N , P-L., S C U L L Y , P., and LEE, to be tightly controlled or maintained for long periods of time. In W-H. (1990). Suppression of tumorigenicity of human prostate addition, the relatively untried nature ofthe technology suggests Viagene, Inc., San Diego, C A 92121.
Ill
112 carcinoma cells by replacing a mutated R B gene. Science 247, 712-715. F R I E D M A N N , T. (1989). Progress toward human gene therapy. Science 244, 1275-1281. M A L I M , M.H., B O H N L E I N , J.H., and C U L L E N , B.R. (1989). Functional dissection of the HIV-1 rev trans-activator—derivation of a trans-dominant repressor of rev function. Cell 58, 205-214. T O W N S E N D , A.R.M., and M c M I C H A E L , A.J. (1985). H L A class I restriction of T cell mediated cytotoxicity. Prog. Allergy 36, 110143.
JOLLY V O N RUDEN,T., and GILBOA, E. (1989). Inhibition of human T-cell leukemia virus type I replication in primary human T cells that express antisense R N A . J. Virol. 63, 677-682. Address reprint requests to: Dr. Douglas J. Jolly Viagene, Inc. 11075 Rose lie Street San Diego, C A 92121
