In lieu of an abstract, here is a brief excerpt of the content:Human Gene TherapyMary Carrington Coutts (bio)On September 14, 1990, researchers at the U.S. National Institutes of Health (NIH) performed the first approved gene therapy procedure on a four-year-old girl named Ashanti DeSilva. Born with a rare genetic disease, severe combined immune deficiency (SCID), Ashanti lacked a healthy immune system and was extremely vulnerable to infection. Children with SCID usually develop overwhelming infections and rarely survive (...) to adulthood; even a common childhood illness like chicken pox is life-threatening. Ashanti led a cloistered existence, avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.In Ashanti's gene therapy procedure, her own white blood cells were genetically modified and then infused back into her bloodstream. Laboratory tests show that the therapy has strengthened Ashanti's immune system. She no longer has recurrent colds, has been allowed to attend school, and has been immunized against whooping cough. This gene therapy procedure is not a cure, however. The genetically-treated white blood cells only survive for a few months and must then be replaced, but Ashanti's future is much brighter because of the new therapy (VI, Thompson [The First] 1993).Although this simplified description of Ashanti's gene therapy procedure sounds like a happy ending, it is little more than an optimistic chapter in a long story. The road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are still many techniques that need to be developed and diseases that need to be understood more fully before gene therapy is well established. The public policy debate surrounding the possible use of genetically engineered material in human subjects is equally complex. Major participants in the debate come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion.In studying the ethics of gene therapy, one should draw a distinction between [End Page 63] therapy on somatic (non-reproductive) cells and germ (reproductive) cells. Only the germ cells carry the genes that will be passed on to the next generation. Reactions to gene therapy have varied widely. Some commentators on gene therapy object to any form of genetic manipulation, no matter how well-intentioned (VI, Rifkin 1983). Another reaction is to allow the use of somatic-cell therapy, but not to approve the use of germ-line therapy, which could have unforeseeable effects on future generations. A different stance is that, with proper regulation and safeguards, germ-line gene therapy is a logical extension of the progress made to date and that it is an ethically acceptable procedure.TechniquesTo date, 43 research protocols have been approved for somatic-cell gene therapy in the United States. The techniques employed in each protocol vary, but in general a virus is used as a "vector" to insert the desired gene into the DNA of the patient's cells, in order to compensate for a defective gene. For Ashanti's gene therapy, this technique involved obtaining white blood cells and introducing properly functioning genes into as many of the cells as possible. The normal genes were delivered through the use of a specially-engineered virus.Although similar techniques are used in germ-line gene therapy, the procedure is more difficult. There are two basic ways to perform germ-line gene therapy: (1) to treat a preimplantation embryo that carries a serious genetic defect before its implantation in the mother, which necessitates the use of in vitro fertilization techniques; or (2) to treat the germ cells (sperm or egg cells) of afflicted adults so that the genetic defects would not be passed on to their offspring, which requires the technical expertise to delete the defective gene and insert a properly functioning replacement. Because of the complexity of the procedures involved and the attendant ethical controversy, germ-line therapy is not currently performed.Candidate Diseases for Gene TherapyAt present, gene therapy is likely to be most successful in treating diseases that are caused by single-gene defects and has been approved for treating diseases such... (shrink)

Despite widespread agreement that it would be ethical to use somatic cell gene therapy to correct serious diseases, there is still uneasiness on the part of the public about this procedure. The basis for this concern lies less with the procedure's clinical risks than with fear that genetic engineering could lead to changes in human nature. Legitimate concerns about the potential for misuse of gene transfer technology justify drawing a moral line that includes corrective germline (...) class='Hi'>therapy but excludes enhancement interventions in both somatic and germline contexts. Keywords: somatic cell, germ line, genetic diseases, genetic engineering, humanness, enhancement, eugenics CiteULike Connotea Del.icio.us What's this? (shrink)

The strength of a slippery slope argument is a matter of some dispute. Some see it as a reasonable argument pointing out what probably or inevitably follows from adopting some practice, others see it as essentially a fallacious argument. However, there seems to be a tendency emerging to say that in many cases, the argument is not actually fallacious, although it may be unsubstantiated. I shall not try to settle this general discussion, but merely seek to assess the strength of (...) the slippery slope argument applied to human gene therapy. The structure of my argument will be the following. First, I shall distinguish between three different versions of the slippery slope argument; two logical versions and an empirical one. Next, I will address human gene therapy in terms of each of the three versions, partly relying on slippery slope arguments against this practice that have already surfaced in the literature. I shall argue that neither version pulls through. The logical versions fail primarily because relevant distinctions can be made between different uses of gene therapy, contrary to what the proponents of the arguments claim. The empirical version fails because there seems to be no evidence supporting the claim that we shall in fact slide down the slope if we engage in gene therapy, and because if we accepted the conclusion that we should not allow gene therapy on the basis of the empirical argument, we should have to make very far-reaching and undesirable modifications in health care in general, in order to be consistent. Or at least so I shall argue. (shrink)

The article investigates the validity of two different versions of the slippery slope argument construed in relation to human gene therapy: the empirical and the conceptual argument. The empirical version holds that our accepting somatic cell therapy will eventually cause our accepting eugenic medical goals. The conceptual version holds that we are logically committed to accepting such goals once we have accepted somatic cell therapy. It is argued that neither the empirical nor the conceptual version (...) of the argument can provide a conclusive moral reason for banning somatic cell therapy. According to a third interpretation, referred to as the arbitrary result argument, the many apparent similarities between somatic cell therapy and eugenic-based human genetic engineering drive us to make principled choices concerning what differences and similarities between the two practices should be regarded as morally (ir)relevant. Decisions of this kind are likely to have unpredictable moral consequences. Thus formulated, the slippery slope argument has much plausibility. One objects to somatic cell therapy not so much because of what is at the bottom of the slope on which it lies, but because it is on a slope of which one does not know what is at the bottom. While the arbitrary result argument does not provide a conclusive reason for prohibiting human gene therapy, it reminds of a very important thing: when making bioethical decisions, we should be as specific and as consistent as possible about our basic moral and medical concepts. (shrink)

Any suggestion of altering the genetic makeup of human beings through gene therapy is quite likely to provoke a response involving some reference to a 'slippery slope'. In this article the author examines the topography of two different types of slippery slope argument, the logical slippery slope and the rhetorical slippery slope argument. The logical form of the argument suggests that if we permit somatic cell gene therapy then we are committed to accepting germ line (...) gene therapy in the future because there is no logically sustainable distinction between them. The rhetorical form posits that allowing somatic cell therapy now will be taking the first step on a slippery slope which will ultimately lead to the type of genocide perpetrated by the Nazis. The author tests the validity of these lines of argument against the facts of human gene therapy and concludes that because of their dependence on probabilities that cannot be empirically proven they should be largely disregarded in the much more important debate on moral line-drawing in gene therapy. (shrink)

types of application of genetic engineering for the insertion of genes into humans. The scientific requirements and the ethical issues associated with each type are discussed. Somatic cell gene therapy is technically the simplest and ethically the least controversial. The first clinical trials will probably be undertaken within the next year. Germ line gene therapy will require major advances in our present knowledge and it raises ethical issues that are now being debated. In order to provide (...) guidelines for determining when germ line gene therapy would be ethical, the author presents three criteria which should be satisfied prior to the time that a clinical protocol is attempted in humans. Enhancement genetic engineering presents significant, and troubling, ethical concerns. Except where this type of therapy can be justified on the grounds of preventive medicine, enhancement engineering should not be performed. The fourth type, eugenic genetic engineering, is impossible at present and will probably remain so for the foreseeable future, despite the widespread media attention it has received. Keywords: genetic engineering, somatic cells, germ cells, enhancement, eugenics, humanhood CiteULike Connotea Del.icio.us What's this? (shrink)

As the potential for the first human trials of somatic cell gene therapy nears, two ethical issues are examined: (1) problems of moral choice for members of institutional review boards who consider the first protocols, for parents, and for the clinical researchers, and the special protections that may be required for the infants and children to be involved, and (2) ethical objections to somatic cell therapy made by those concerned about a putative inevitable progression of genetic (...) knowledge from therapy to mass genetic engineering in human reproduction. The author's viewpoint is that a consensus exists on the required moral approach to somatic cell therapy, but that no moral approach yet exists for experiments beyond this level, especially in the germline cells of human beings. Keywords: gene therapy, somatic cells, germ cells, institutional review boards, genetic engineering CiteULike Connotea Del.icio.us What's this? (shrink)

The concept of human gene therapy came on the heels of fundamental discoveries on the nature and working of the gene. However, realistic prospects to correct the underlying cause of recessive genetic disorders through the transfer of wild‐type alleles of defective genes had to wait for the arrival of recombinant DNA technology. These techniques permitted the isolation and insertion of genes into the first recombinant delivery systems. The realization that viruses are natural gene carriers provided (...) inspiration for gene therapy and, as engineered vectors, viruses became prominent gene delivery vehicles. Nonetheless, when put in the context of human and non‐human primate studies, all vectors fell short of success regardless of their viral or non‐viral origin. Recognition of issues such as inefficient gene transfer and short‐lived or scant expression in the relevant cell type(s) prompted researchers to refine and develop several gene delivery systems, in particular those based on retroviruses, adeno‐associated viruses and adenoviruses. Concomitantly, available technology was deployed to tackle disorders that require few genetically corrected cells to attain therapy. BioEssays 27: 506–517, 2005. © 2005 Wiley periodicals, Inc. (shrink)

Recent political developments and disclosures of serious adverse events in human gene therapy (HGT) with the death of 18‐year old Jesse Gelsinger in the USA have shown that the clinical application of HGT raises some severe ethical issues. These have either been neglected or not yet been discussed to a satisfactory extent. In this paper, we will address this deficiency and develop strategies for a safer application of HGT. Such a study must first look closely at the (...) science of HGT itself. We will evaluate the latest preclinical research, especially data on the viruses that are used as vectors and on modes of administration of vectors. We will put forward new arguments concerning the toxicity assessment of so‐called ‘gene drugs‘, the tissue and cell type specificity of the vectors, and the duration and on‐set of gene expression. Secondly, we will look at procedural aspects of applied research ethics on the way to clinical application of HGT. There, informed consent (IC) and the patient‐researcher relationship are of utmost concern. Furthermore, we will explore the problem of expertise in risk assessment and will show how current regulations foster conflicts of interests that create dilemma situations even for those researchers who act in the best interest of the patients. We will conclude the article with a set of questions for ethicists who have to decide about the quality of HGT protocols. This may contribute to the safety of patients participating in HGT trials and to achieving the aim of efficient application of HGT. (shrink)

The prelims comprise: Introduction A (re)Defmition of what Human Gene Therapy is About Neurological Gene Therapy Ethics and Gene Therapy Acknowledgments Notes.

The case in favor of gene therapy is quite simple. Gene therapy is likely to improve the health and well-being of some people that are among the worst off in society, namely patients with painful and life-threatening diseases. However, two types of objection have been raised.

Oversight of human gene transfer research presents an important model with potential application to oversight of nanobiology research on human participants. Gene therapy oversight adds centralized federal review at the National Institutes of Health's Office of Biotechnology Activities and its Recombinant DNA Advisory Committee to standard oversight of human subjects research at the researcher's institution and at the federal level by the Office for Human Research Protections. The Food and Drug Administration's Center for (...) Biologics Evaluation and Research oversees human gene transfer research in parallel, including approval of protocols and regulation of products. This article traces the evolution of this dual oversight system; describes how the system is already addressing nanobiotechnology in gene transfer: evaluates gene therapy oversight based on public opinion, the literature, and preliminary expert elicitation; and offers lessons of the gene therapy oversight experience for oversight of nanobiotechnology. (shrink)

As a philosopher interested in biomedical ethics, I find recent advances in genetic technologies both fascinating and frightening. Future technologies for genetic therapies and elimination of clearly deleterious genes offer us the ability to get rid of the cause of much human suffering, seemingly at its physiological root. But memories of past eugenics programs gone horribly awry must make cautious our initial optimism for these generally well-intentioned programs. Most often the scientist proceeds in research with the best of intentions, (...) but that does not make all scientific investigation worth pursuing. (shrink)

The prelude to successful human somatic gene therapy, i.e. the efficient transfer and expression of a variety of human genes into target cells, has already been accomplished in several systems. Safe methods have been devised to do this using non‐viral and viral vectors. Potentially therapeutic genes have been transferred into many accessible cell types, including hematopoietic cells, hepatocytes and cancer cells, in several different approaches to ex vivo gene therapy. Successful in vivo gene (...) therapy requires improvements in tissuetargeting and new vector design, which are already being sought. Gene‐transfer protocols have been approved for human use in inherited diseases, cancer and acquired disorders. Althouth the results of these trials to date have been somewhat disappointing, human somatic cell gene therapy promises to be an effective addition to the arsenal of approaches to the therapy of many human diseases in the 21st century if not sooner. (shrink)

To discern the ethical issues involved incurrent gene therapy research, to explore theproblems inherent in possible future genetherapies, and to encourage debate within thescientific community about ethical questionsrelevant to both, we surveyed American Societyof Human Genetics scientists who engage inhuman genetics research. This study of theopinions of U.S. scientific experts about theethical issues discussed in the literature ongene therapy contributes systematic data on theattitudes of those working in the field as wellas elaborative comments. Our survey finds (...) thatrespondents are highly supportive of thepotential use of somatic cell gene therapy tocure serious diseases in adults and children aswell as prospective offspring. A clearmajority, however, believe that using suchgenetic techniques for enhancement purposes isunacceptable. Delineating the line betweendisease/disorder and improvement/enhancementposes a problem not easily resolved and oneconducive to the growth of slippery-slopeapprehensions. The majority of respondents alsoadvocate germ-line therapy, in theory at least,and under similar restrictions, but theyrecognize the roadblock that the existence ofunanticipated negative consequences currentlypresents. Another complex matter involvestrying to determine appropriate reasons forchoosing target diseases for research, forwhich the dichotomy between rare single-geneand common multifactorial diseases reveals anongoing dilemma. (shrink)

The prelims comprise: Germline Gene Therapy Genetic Enhancements The Genome and the Normative Status of Human Nature Conclusion Notes.

This paper reports on the meeting of the Sounding Board of the EU Reprogenetics Project that was held in Budapest, Hungary, 6–9 November 2005. The Reprogenetics Project runs from 2004 until 2007 and has a brief to study the ethical aspects of human reproductive cloning and germline gene therapy. Discussions during The Budapest Meeting are reported in depth in this paper as well as the initiatives to involve the participating groups and others in ongoing collaborations with the (...) goal of forming an integrated network of European resources in the fields of ethics of science. (shrink)

Gene therapy is the modification of the human genetic code to prevent disease or cure illness. This technology is in its infancy and remains confined to experimental clinical trials. Once the present barriers are overcome, gene therapy will confront humanity with a host of ethical challenges. Therapies targeted to the genes of germ-line cells will introduce permanent changes to the human gene pool. Furthermore, nonmedical gene modifications have the potential to introduce a (...) new form of eugenics into our society by which some members attempt to become inherently superior to others and humanity is re-engineered to man-made specifications. National Catholic Bioethics Quarterly 10.1 (Spring 2010): 45–50. (shrink)

Neuwelt et al. have proposed gene-transfer experiments utilizing an animal model that offers many important advantages for investigating the feasibility of gene therapy in the human brain. A variety of tissues concerning the viral vector and mode of delivery of the corrective genes need to be resolved, however, before such therapy is scientifically supportable.

Aldehyde dehydrogenase 2 (ALDH2) deficiency constitutes one of the most common hereditary enzyme deficiencies, affecting 35% to 40% of East Asians and 8% of the world population. It causes the well-known Asian Alcohol Flush Syndrome, characterized by facial flushing, palpitation, tachycardia, nausea, and other unpleasant feelings when alcohol is consumed. It is also associated with a marked increase in the risk of a variety of serious disorders, including esophageal cancer and osteoporosis. Our recent studies with murine models have demonstrated that (...) a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) will correct the deficiency state and prevent alcohol-induced abnormalities of the esophagus and bone. If successful in humans, such strategy would reduce the increased risk-associated disorders such as esophageal cancer and osteoporosis, but also prevent the Asian Alcohol Flush Syndrome. This treatment thus raises ethical concerns: although it would potentially prevent fatal disease, it could also allow affected individuals to drink alcohol without suffering the Asian Alcohol Flush Syndrome and, hence, potentially enable personal destructive behavior. Here we explore the ethical arguments against the development of a gene therapy for ALDH2 deficiency and we find them wanting. We contend that development of such treatments is ethically appropriate and should be part and parcel of the solutions offered against the condition. (shrink)

It may be possible, one day, to use gene therapy to treat diseases whose genetic defects have been discerned. Because many genes responsible for inherited eye disorders within the retina have been identified, diseases of the eye are prime candidates for this form of therapy. The eye also has the advantage of being highly accessible with altered immunological properties, important considerations for easy delivery of virus and avoidance of systemic immune responses. Currently, adenovirus, adeno‐associated virus and lentivirus (...) have been used to successfully transfer genetic material to retinal pigment epithelium and photoreceptor cells. By harnessing therapeutic genes to these viruses, researchers have been able to demonstrate rescue in rodent models of retinitis pigmentosa, providing evidence that this form of therapy can be effective in delaying photoreceptor cell death. Future challenges include confirming therapeutic effects in animal models with eyes more anatomically similar to those of humans and demonstrating long‐term rescue with minimal toxicity. BioEssays 23:662–668, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This book provides a worthwhile and challenging introduction to scientific and moral issues in germline gene therapy. It contains two parts, dealing with scientific and moral issues respectively. In the first, scientific part, a chapter on what the alternatives to germline therapy are is helpful, especially in pointing out that many of the goals one might want to achieve by using germline therapy may be achieved, at a slighter risk, by using non-genetic technologies such as selective (...) embryo implantation and selective abortion. However, the authors argue that germline therapy may be an option in certain cases in which these alternatives are not viable (page 72). In the second part of the book, moral and political issues in germline therapy are discussed, such as the distinction between therapy and enhancement, potential benefits and harms, rights and responsibilities, justice, our concept of humanness, and public policy issues. The …. (shrink)

This paper attempts to debunk the slippery-slope argument against human germ-line gene therapy by showing that the downside of the slope – genetic enhancement – need not be as unethical or unjust as some people have supposed. It argues that if genetic enhancement is governed by proper regulations and is accompanied by adequate education, then it need not violate recognized principles of morality or social justice. Keywords: germ-line therapy, slippery slope argument, future generations, social justice CiteULike (...) Connotea Del.icio.us What's this? (shrink)

The article combines a criticism of public understanding of science with the sociology of expectations to examine how particular expectations toward scientific progress have performative effects for the construction of publics as citizens of science. By analyzing a particular controversy about gene therapy in Denmark, the article demonstrates how different sets of expectations can be used to discriminate among three different assemblages: the assemblage of consumption, the assemblage of comportment, and the assemblage of heroic action. Each of these (...) assemblages makes medical science, scientific citizenship, politics, patients, doctors, and expectations toward the future emerge in particular ways. By their radically different expectations toward science and their different constructions of what it means to be a scientific citizen, the assemblages construct the objectives of the governance of science in three very different ways. (shrink)

Germ-line gene therapy, like many other medical technologies, raises questions of special concern to Christians. It not only raises questions about medical effects, actual or possible, of genetic interventions that would be inherited from one generation to another but also, more importantly, raises anthropological questions and so questions about parental attitudes. These are questions about the dignity and value of human life, about inter-human relations and about the God-human relationship.1 For this reason the paper starts (...) with an exploration of the implications of Christian anthropology, viewed from a Roman Catholic perspective. A set of conditions will be specified in the light of which germ-line gene therapy’s compatibility with Christian attitudes, a Christian understanding of the human being, and the meaning of human life can be assessed. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the (...) transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

Although the ability to perform gene therapy in human germ-line cells is still hypothetical, the rate of progress in molecular and cell biology suggests that it will only be a matter of time before reliable clinical techniques will be within reach. Three sets of arguments are commonly advanced against developing those techniques, respectively pointing to the clinical risks, social dangers and better alternatives. In this paper we analyze those arguments from the perspective of the client-centered ethos that (...) traditionally governs practice in medical genetics. This perspective clarifies the merits of these arguments for geneticists, and suggests useful new directions for the professional discussion of germ-line gene therapy. It suggests, for example, that the much discussed prospect of germ-line therapy in human pre-embryos may always be more problematic for medical genetics than adult germ-line interventions, even though the latter faces greater technical difficulties. (shrink)

Abstract:There is a role for regulatory oversight over new genetic technologies. Research must ensure the rights of human subjects, and all medical products and techniques should be ensured to be safe and effective. In the United States, these forms of regulation are largely the purview of the National Institutes of Health and the Food and Drug Administration. Some have argued, however, that human genetic therapies require new regulatory agencies empowered to enforce cultural norms, protect against hypothetical social harms, (...) or ensure that the human genome remains unchanged. Focusing on the United States, this essay will briefly review these arguments and argue that the current limited regulatory role over human gene therapies is sufficient to protect public health, bodily autonomy, and reproductive freedom. (shrink)

The recent tragic and widely publicised death of Jesse Gelsinger in a gene therapy trial has many important lessons for those engaged in the ethical review of research. One of the most important lessons is that ethics committees can give too much weight to ensuring informed consent and not enough attention to minimising the harm associated with participation in research. The first responsibility of ethics committees should be to ensure that the expected harm associated with participation is reasonable. (...) Jesse was an 18-year-old man with a mild form of ornithine transcarbamylase (OTC) deficiency, a disorder of nitrogen metabolism. His form of the disease could be controlled by diet and drug treatment. On September 13 1999 a team of researchers lead by James Wilson at the University of Pennsylvania's Institute for Human Gene Therapy (IHGT) injected 3.8 X 1013 adenovirus vector particles containing a gene to correct the genetic defect. He was the eighteenth and final patient in the trial. The virus particles were injected directly into the liver. He received the largest number of virus particles in a gene therapy trial.1 Four days later he was dead from what was probably an immune reaction to the virus vector. This was the first death directly attributed to gene therapy. It resulted in worldwide publicity, an independent investigation, the Federal Drug Administration (FDA) suspending all trials at the IHGT, an FDA, and a senate subcommittee investigation. At a special public meeting at the National Institutes of Health (NIH) in December 1999, James Wilson, also the director of the IHGT, said they still did not understand fully what had gone wrong.2 Even though a massive dose had been used, only 1% of transferred genes reached the target cells. (None of the patients in the trial showed significant gene expression. Art …. (shrink)

Human UDP‐glucuronosyltransferases (UDPGTs) are a family of enzymes which detoxify many hundreds of compounds by their conjugation to glucuronic acid, rendering them both harmless and more water soluble, hence, excretable. The level of expression of each UDPGT isoform in the body is the result of interplay between temporal, tissue‐specific and environmental regulators. This complexity contributes to the difficulty in predicting the metabolic fate of compounds.Genetic defects and polymorphisms affecting individual isoform activities have deleterious and potentially lethal effects, as exemplified (...) by the severe hyperbilirubinaemia observed in Crigler‐Najjar Syndrome. Such severe genetic defects in bilirubin glucuronidation are obvious candidates for antenatal screening and gene therapy. (shrink)

In 1956, I decided to apply my experience in microbial genetics to developing analogous systems for human cell lines, including the selection of mutants with either a loss or gain of a biochemical function. For instance, mutants resistant to azahypoxanthine showed a loss of the HPRT enzyme (hypoxanthine phosphoribosyl transferase), whereas gain of the same enzyme was accomplished by blocking de novo purine biosynthesis with aminopterin, while supplying hypoxanthine and thymine (HAT selection). Using HAT selection, we: (i) genetically transformed (...) HPRT− mutant cells to HPRT+ wild type by using DNA extracted from HPRT+ cells, and (ii) selected HPRT+ hybrid cells by fusing HPRT− D98/AH2 cells with skin cells. These approaches, which we dubbed in 1962 as a [first step toward gene therapy], contributed to the later development of (i) cell fusion techniques, (ii) the development of monoclonal antibodies, (iii) routine transformation of mammalian cells with cloned genes, and (iv) methods for creating transgenic organisms. (shrink)

In March 1996, the General Accounting Office issued the report Scientific Research: Continued Vigilance Critical to Protecting Human Subjects. It stated that “an inherent conflict of interest exists when physician-researchers include their patients in research protocols. If the physicians do not clearly distinguish between research and treatment in their attempt to inform subjects, the possible benefits of a study can be overemphasized and the risks minimized.” The report also acknowledged that “the line between research and treatment is not always (...) clear to clinicians. Controversy exists regarding whether certain medical procedures should be categorized as research.”This problem currently plagues gene transfer research. A few months prior to the GAO report, an ad hoc committee appointed by National Institutes of Health Director Harold Varmus expressed similar concerns in its assessment of NIH investment in research on gene therapy. (shrink)

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the (...) transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

In March 1996, the General Accounting Office (GAO) issued the reportScientific Research: Continued Vigilance Critical to Protecting Human Subjects.It stated that “an inherent conflict of interest exists when physician-researchers include their patients in research protocols. If the physicians do not clearly distinguish between research and treatment in their attempt to inform subjects, the possible benefits of a study can be overemphasized and the risks minimized.” The report also acknowledged that “the line between research and treatment is not always cleartoclinicians. (...) Controversy exists regarding whether certain medical procedures should be categorized as research.”This problem currently plagues gene transfer research. A few months prior to the GAO report, an ad hoc committee appointed by National Institutes of Health (NIH) Director Harold Varmus expressed similar concerns in its assessment of NIH investment in research on gene therapy. (shrink)

BackgroundHIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale.MethodsTo elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the (...) United States: (1) biomedical HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants’ perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure.ResultsWe interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions.ConclusionOur study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers. (shrink)

Recombinant DNA technology will soon allow physicians an opportunity to carry out both somatic cell- and Germ-Line gene therapy. While somatic cell gene therapy raises no new ethical problems, gene therapy of gametes, fertilized eggs or early embryos does raise several novel concerns. The first issue discussed here relates to making a distinction between negative and positive eugenics; the second issue deals with the evolutionary consequences of lost genetic diversity. In distinguishing between positive and (...) negative eugenics, the concept of malady is applied as a definitional criterion for identifying genetic disorders that could qualify for Germ-Line therapy. Because gene replacement techniques are currently unavailable for humans, and because even if they were possible the number of people involved would be quite small, the loss of diversity concern seems moot. Finally, we dissuss the issue of iatrogenic disorders associated with gene therapy and discuss several ‘real world considerations.’. (shrink)