Gene transfer represents a relatively new possibility for the treatment of rare genetic disorders and common multifactorial diseases by changing the expression of a person's genes. Typically gene transfer involves using a vector such as a virus to deliver a therapeutic gene to the appropriate target cells. The technique, which is still in its infancy and is not yet available outside clinical trials, was originally envisaged as a treatment of monogenic disorders, but the majority of trials now involve the treatment of cancer, infectious diseases and vascular disease. Human gene transfer raises several important ethical issues, in particular the potential use of genetic therapies for genetic enhancement and the potential impact of germline gene transfer on future generations.
Gene transfer can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene transfer the recipient's genome is changed, but the change is not passed on to the next generation. In germline gene transfer, the parents' egg and sperm cells are changed with the goal of passing on the changes to their offspring. Germline gene transfer is not being actively investigated, at least in larger animals and humans, although a great deal of discussion is being conducted about its value and desirability.
Many people falsely assume that germline gene transfer is already routine. For example, news reports of parents selecting a genetically tested egg for implantation or choosing the sex of their unborn child may lead the public to think that gene transfer is occurring, when actually, in these cases, genetic information is being used for selection, with no cells being altered or changed. In addition, in 2001 scientists confirmed the birth of 30 genetically altered children whose mothers had undergone a procedure called ooplasmic transfer. In this process, doctors injected some of the contents of a healthy donor egg into an egg from a woman with infertility problems. The result was an egg with two types of mitochondria, cellular structures that contain a minuscule amount of DNA and that provide energy for the cell. The children born following this procedure thus have three genetic parents, since they carry DNA from the donor as well as the mother and father. Although the researchers announced this as the "first case of human germline genetic modification," the gene transfer was an inadvertent side effect of the infertility procedure.
Many factors have prevented researchers from developing successful gene transfer techniques in both somatic and germline attempts (the latter in animals). The first hurdle is the gene delivery tool. The new gene is inserted into the body through vehicles called vectors (gene carriers), which deliver therapeutic genes to the patients' cells. Currently, the most common vectors are viruses, which have evolved a mechanism to encapsulate and deliver their genes to human cells in a pathogenic manner. Scientists have tried to take advantage of the virus's biology and manipulate its genome to remove human disease-causing genes and insert therapeutic genes. However, viruses, while effective, introduce other problems to the body, such as toxicity, immune and inflammatory responses, and gene control and targeting issues. Complexes of DNA with lipids and proteins provide an alternative to viruses, and researchers are also experimenting with introducing a 47th (artificial human) chromosome to the body that would exist autonomously along side the standard 46 chromosomes, presumably not affecting their functioning or causing any mutations. An additional chromosome would be a large vector capable of carrying substantial amounts of genetic code, and it is anticipated that, because of its construction and autonomy, the body's immune systems would not attack it.
Some of the concerns raised about somatic gene transfer are related to the possibility that it could inadvertently lead to germline gene transfer. The possibility of germline modification through these techniques is the result of the hit-or-miss nature of the current technologies. It is always possible that a vector will introduce the gene into a cell other than that for which it is supposed to be targeted (e.g., a spermatocytic cell) or that through a secondary mechanism target cells that have taken up the new gene will through some independent natural process (such as transfection) transfer the gene to a germline cell. Moreover, if somatic gene transfer were to be conducted in utero, especially before the second trimester, it would increase the likelihood that some of the cells into which the gene is taken up will become part of the germline. It is possible that to effectively treat certain diseases using gene transfer, it might be necessary to apply somatic techniques early in development so that germline transfer is inevitable.
In contrast to inadvertent germline transfer following somatic gene transfer, intentional germline gene transfer would involve the deliberate introduction of new genetic material into either germ cells (sperm or oocytes) or into zygotes in vitro prior to fertilization or implantation. Currently, this technology has not been applied to humans; however, it has been successfully applied to some plants and animals. The aim of this process is to produce a developing embryo in which each cell (including those that will develop into gametes in the future) carries the newly inserted gene as part of its genetic make-up.
Current efforts in animals have demonstrated the difficulty of this approach. Some cells do not acquire the gene or acquire multiple or partial copies of the gene. In addition, it is not yet possible to specify with any accuracy where in the genome the new gene will be introduced, and some insertion locations may interfere with other important genes. If these kinds of errors are detected, then theoretically embryos with these defects could be "selected out." However, should germline gene transfer be attempted in humans, it is likely that not all errors introduced as a result of the gene transfer will be detected.
Currently, however, animal studies have shown that gene transfer approaches that involve the early embryo can be far more effective than somatic cell gene therapy methodologies used later in development, depending on the complexity of the trait that is being improved or eliminated. Embryo gene transfer affords the opportunity to transform most or all cells of the organism and thus overcome the inefficient transformation that plagues somatic cell gene transfer protocols. Gene transfer selects one relevant locus for a trait (when in fact there might be many interactive loci) and then attempts to improve the trait in isolation. This approach, while potentially more powerful and efficient than conventional breeding techniques, involves more uncertainty risks.
Thus, both kinds of studies - germline gene transfer at the gamete and zygote stages - have significant risks. In cases in which the gene has failed to be introduced or fails to be activated, the resulting child would likely be no worse off than he or she would have been without the attempted gene transfer. However, those with partial or multiple copies of a gene could be in significantly worse condition. The problems resulting from errors caused by the gene insertion could be severe - even lethal - or they might not be evident until well after the child has been born, perhaps even well into adulthood, when the errors could be passed on to future generations. For these reasons, given the limits of current technology, germline gene transfer has been considered ethically impermissible.
Beyond the medical risks to the potential child, a number of long-standing ethical concerns exist regarding the possible practice of germline gene transfer in both human and nonhuman cases. Such modifications in human beings raise the possibility that we are changing not merely a single individual but a host of future individuals as well, with potential for harm to occur to those individuals and perhaps to humanity as a whole. Concerns involve issues ranging from the autonomy of future individuals to distributive justice, fairness, and the application of these technologies to "enhancement" rather than treating disease. In germline gene transfer, the persons being affected by the procedure - those for whom the procedure is undertaken - do not yet exist. Thus, the potential beneficiaries are not in a position to consent to or refuse such a procedure.
Gene transfer clinical trials have a unique oversight process that is conducted by the National Institutes of Health (NIH) through the Recombinant DNA Advisory Committee (RAC) and the NIH Guidelines for Research Involving Recombinant DNA Molecules, and by the Food and Drug Administration (FDA) through regulation (including scientific review, regulatory research, testing, and compliance activities, including inspection and education). Of note, FDA regulations apply to all clinical gene transfer research, while NIH governs gene transfer research that is supported with NIH funds or that is conducted at or sponsored by institutions that receive funding for recombinant DNA research. Currently, the majority of somatic cell gene transfer research is subject to the NIH Guidelines; however RAC will not currently consider protocols using germline gene transfer.
In addition, NIH has added to its guidelines the following statement:
The RAC continues to explore the issues raised by the potential of in utero gene transfer clinical research. However, the RAC concludes that, at present, it is premature to undertake any in utero gene transfer clinical trial. Significant additional preclinical and clinical studies addressing vector transduction efficacy, biodistribution, and toxicity are required before a human in utero gene transfer protocol can proceed. In addition, a more thorough understanding of the development of human organ systems, such as the immune and nervous systems, is needed to better define the potential efficacy and risks of human in utero gene transfer. Prerequisites for considering any specific human in utero gene transfer procedure include an understanding of the pathophysiology of the candidate disease and a demonstrable advantage to the in utero approach. Once the above criteria are met, the RAC would be willing to consider well rationalized human in utero gene transfer clinical trials.
Prepared by Kathi E. Hanna, M.S., Ph.D., Science and Health Policy Consultant
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Last Reviewed: March 2006