H U M A N G E N E T H E R A P Y 1:111-123 (1990) Mary Ann Liebert, Inc., Publishers
Safety Considerations in S o m a t i c G e n e T h e r a p y o f H u m a n D i s e a s e with Retrovirus Vectors
H O W A R D M. TEMIN
ABSTRACT Somatic gene therapy of human disease with retrovirus vectors is a new technology with potentially important medical benefits. Although it involves recombinant D N A technologies and modified retroviruses, proper design ofthe vectors and delivery systems removes most potential foreseen risks. Furthermore, even in the very remote possibility that there is a nontherapeutic biological effect ofthe treatment, it is unlikely to be a harmful one. Thus, once very safe retrovirus vector-helper cell systems are constructed and in use, safety considerations should not hold up further h u m a n trials of retrovirus vectors.
OVERVIEW S U M M A R Y Safety is the primary issue that must be evaluated by the regulatory committees who have the responsibility for reviewing h u m a n gene therapy clinical protocols. Temin provides an overall view of the safety issues associated with retroviral-mediated gene transfer from the perspective of a pioneer in retrovirus biology.
INTRODUCTION There are OFTEN unexpected effects of new technologies. Thus, the safety of somatic gene therapy of human disease with retrovirus vectors needs to be discussed in detail. The use of retrovirus vectors for somatic therapy of human genetic diseases can be looked upon as either a novel improvement on present means of drug delivery or as the introduction of a potentially dangerous technology. Although scientists and physicians may believe that the first characterization is correct, I a m convinced that w e must act as if the second characterization is correct. W e must design vector systems and protocols so that even quite unrealistic fears about safety are allayed. The general plan most frequently discussed for somatic gene therapy of human disease with retrovirus vectors is to use a retrovirus vector to introduce a functional replacement for a gene that is absent or misfunctioning in the patient. A helper virus-free retrovirus vector will be used to infect bone marrow cells from the patient. (There is also discussion of infection of other tissues.) After selection for successful
McArdle Laboratory, University of Wisconsin, Madison, W I 53706. Ill
TEMIN infection, the infected cells or tissues will be transplanted back into the patient (Anderson, 1984; Parkman, 1986; Friedman, 1989). All of the therapies n o w being considered involve only somatic cells and not germ-line cells. However, since germ-line genetic engineering with retrovirus vectors has begun in chickens and mice (Salter et aL, 1987; Bosselman et al., 1989a,b), it will have to be discussed for humans. Concerns W h o s e safety are w e concerned with in considering somatic therapy of human diseases with retrovirus vectors? First, the patients' The new therapy should not harm the patients. Possible types of harm to patients from somatic gene therapy of human disease with retrovirus vectors include induction of an increasedriskof cancer, induction of other harmful mutations, exposure to infectious viruses resulting from the therapy, exposure to massive amounts of publicity, other general concerns, and unforeseen complications. Questions relevant to these concerns are whether or not they are lessened when the patients have an extremely severe, life-threatening disease and whether or not they are heightened when the patients are minors. Second, the n e w therapy should not do harm to health care workers and other care givers, including the patients' families. Possible types of harm to persons in close contact with patients undergoing retrovirus somatic gene therapy include infection by infectious viruses resulting from the therapy, legal liability, problems in coping with medical and psychological complications in the patients, bad publicity, and unforeseen complications. Third, the new therapy should not result in harm to the general population. W e need to consider the possibility of formation of a novel and infectious virus [related to the vector or not (Seale, 1989)] during somatic gene therapy of human disease with retrovirus vectors, the costs of such therapy, the possible evolutionary effects of such therapy (by means such as inadvertent infection ofthe patient's germ-line), and unforeseen complications. Characteristics of the safest possible retrovirus vector system A retrovirus vector-helper cell system, like any other genetic system, is subject to mutation and selection and contamination. In addition, retrovirus vectors have certain intrinsic properties that make them good vectors, but they also have other intrinsic properties that introduce potential problems to their use as vectors. These intrinsic potential problems cannot be removed by better design of the vectors. The safest possible retrovirus vector system would involve a vector containing the minimal amount of retrovirus sequences required for transcription of vector R N A , packaging of vector R N A , reverse transcription of vector R N A , and integration of vector D N A . These sequences are only R-U5-
Safety Considerations in S o m a t i c G e n e T h e r a p y o f H u m a n D i s e a s e with Retrovirus Vectors
H O W A R D M. TEMIN
ABSTRACT Somatic gene therapy of human disease with retrovirus vectors is a new technology with potentially important medical benefits. Although it involves recombinant D N A technologies and modified retroviruses, proper design ofthe vectors and delivery systems removes most potential foreseen risks. Furthermore, even in the very remote possibility that there is a nontherapeutic biological effect ofthe treatment, it is unlikely to be a harmful one. Thus, once very safe retrovirus vector-helper cell systems are constructed and in use, safety considerations should not hold up further h u m a n trials of retrovirus vectors.
OVERVIEW S U M M A R Y Safety is the primary issue that must be evaluated by the regulatory committees who have the responsibility for reviewing h u m a n gene therapy clinical protocols. Temin provides an overall view of the safety issues associated with retroviral-mediated gene transfer from the perspective of a pioneer in retrovirus biology.
INTRODUCTION There are OFTEN unexpected effects of new technologies. Thus, the safety of somatic gene therapy of human disease with retrovirus vectors needs to be discussed in detail. The use of retrovirus vectors for somatic therapy of human genetic diseases can be looked upon as either a novel improvement on present means of drug delivery or as the introduction of a potentially dangerous technology. Although scientists and physicians may believe that the first characterization is correct, I a m convinced that w e must act as if the second characterization is correct. W e must design vector systems and protocols so that even quite unrealistic fears about safety are allayed. The general plan most frequently discussed for somatic gene therapy of human disease with retrovirus vectors is to use a retrovirus vector to introduce a functional replacement for a gene that is absent or misfunctioning in the patient. A helper virus-free retrovirus vector will be used to infect bone marrow cells from the patient. (There is also discussion of infection of other tissues.) After selection for successful
McArdle Laboratory, University of Wisconsin, Madison, W I 53706. Ill
TEMIN infection, the infected cells or tissues will be transplanted back into the patient (Anderson, 1984; Parkman, 1986; Friedman, 1989). All of the therapies n o w being considered involve only somatic cells and not germ-line cells. However, since germ-line genetic engineering with retrovirus vectors has begun in chickens and mice (Salter et aL, 1987; Bosselman et al., 1989a,b), it will have to be discussed for humans. Concerns W h o s e safety are w e concerned with in considering somatic therapy of human diseases with retrovirus vectors? First, the patients' The new therapy should not harm the patients. Possible types of harm to patients from somatic gene therapy of human disease with retrovirus vectors include induction of an increasedriskof cancer, induction of other harmful mutations, exposure to infectious viruses resulting from the therapy, exposure to massive amounts of publicity, other general concerns, and unforeseen complications. Questions relevant to these concerns are whether or not they are lessened when the patients have an extremely severe, life-threatening disease and whether or not they are heightened when the patients are minors. Second, the n e w therapy should not do harm to health care workers and other care givers, including the patients' families. Possible types of harm to persons in close contact with patients undergoing retrovirus somatic gene therapy include infection by infectious viruses resulting from the therapy, legal liability, problems in coping with medical and psychological complications in the patients, bad publicity, and unforeseen complications. Third, the new therapy should not result in harm to the general population. W e need to consider the possibility of formation of a novel and infectious virus [related to the vector or not (Seale, 1989)] during somatic gene therapy of human disease with retrovirus vectors, the costs of such therapy, the possible evolutionary effects of such therapy (by means such as inadvertent infection ofthe patient's germ-line), and unforeseen complications. Characteristics of the safest possible retrovirus vector system A retrovirus vector-helper cell system, like any other genetic system, is subject to mutation and selection and contamination. In addition, retrovirus vectors have certain intrinsic properties that make them good vectors, but they also have other intrinsic properties that introduce potential problems to their use as vectors. These intrinsic potential problems cannot be removed by better design of the vectors. The safest possible retrovirus vector system would involve a vector containing the minimal amount of retrovirus sequences required for transcription of vector R N A , packaging of vector R N A , reverse transcription of vector R N A , and integration of vector D N A . These sequences are only R-U5-
