Gene Therapy Research Paper

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Gene therapy is a significant preclinical and clinical research area of medical genetics. As such, there are important elements of bioethics that require the attention of researchers engaged in clinical research involving gene therapies. The field of medical genetics continues to develop with varied techniques and methods designed for translation from laboratory to bedside. This research paper reviews developments and identifies various ethical issues associated with various modalities of gene therapy.


Modern genetics informs us of the biological basis of human life – the human genome – explaining elements of both the diversity and the variability of human populations and individuals. This genetic variability relates causally to patterns of infection and disease that affect both individuals and particular population groups. The field of medical genetics is a dynamic area of contemporary biomedical research and medical care, adding to our knowledge and treatment of heritable conditions and diseases that are caused by abnormalities in single genes (e.g., beta-thalassemia, hemophilia, sickle cell anemia), chromosomes (e.g., Down syndrome, Klinefelter syndrome), somatic cells (e.g., cancers of various types), and mitochondrial DNA (e.g., muscular dystrophy, mitochondrial encephalopathy, Leigh syndrome) (Kresina 2004; Kimmelman 2009).

A genetic condition can be expressed in an individual as a genetic disorder or disability. Research in medical genetics includes both a basic science focus designed to understand the cellular-level mechanisms of such disorders and a more applied type of research (applied human genetics) that develops an assortment of recombinant techniques manipulating cell components. Modification can proceed for various purposes, including procedures not discussed here, viz., genetic enhancement and reproductive cloning (Kiuru and Crystal 2008).

History And Development: Background Of The Issue

Techniques designed to treat genetic conditions are commonly referred to as gene therapy. Gene therapy involves the use of procedures designed to insert a functional gene at a site in an individual’s body where the gene is lacking. It is the absence of the gene that has the consequence of impairment in some physiological function (Encyclopedia 2014). The hope of such therapy is to reduce both the burden of genetic conditions or diseases in a population (i.e., rates of disease frequency or morbidity, including both late-onset incidence and prevalence) and deaths (rates of mortality) due to these conditions. In addition to the basic science of medical genetics, epidemiological studies of genetic conditions (sometimes called “genomic epidemiology”) are often undertaken in relation to public health goals in particular populations.

Gene therapy had its beginning in the 1960s and 1970s, with the first human gene transfer occurring in 1990 in the USA in a 4-year-old Ashanti DeSilva, who suffered from ADA (adenosine deaminase enzyme) deficiency. This is a disorder which manifests as an immune system deficiency (Wirth et al. 2013). DeSilva’s gene transfer was successful with about 20–25 % of leukocytes having the desired gene, although she has continued on with enzyme replacement as part of the management of her condition. Since then, scientists have continued the development of various methods. It has been reported that by 2004 there were over 700 gene therapy protocols initiated worldwide, with over 600 serious adverse events reported. Some of these events have been due to noncompliance with clinical protocol and regulatory requirements, while other events have been due to the difficulty of predicting side effects of gene therapy (e.g., autoimmune responses) (Spink and Geddes 2004).

Ledley et al. (2014) opine that the field of gene therapy has matured steadily since the 1980s, as they report over 35,000 scientific papers, over 16,000 patents (USA), over 1,800 clinical trials, and a significant capital expenditure for research exceeding US$4.3 billion by companies investing in gene therapy. Hence, there is significant research endeavor with anticipated ongoing translation of research results into the clinical setting of patient care.

Conceptual Clarification/Definition

Gene therapy includes three primary modalities – somatic cell therapy (intended to correct, and thus cure, a genetic disorder in a given individual), germ-line therapy (intended to eliminate a genetic disorder by removing the prospect of its transmission from one generation to another), and therapies involving expression of genes. Some chronic degenerative diseases (e.g., hypertension, diabetes) that are suspected to have multifactorial or polygenic causation are thought to be prospective candidates for gene therapy, although the fact of polygenic causation creates additional problems about predicting both safety and efficacy. Germ-line therapy (i.e., the genetic manipulation or modification of human gametes, zygotes, or embryos) is not now permitted by international guidelines, and national legislation in most countries explicitly limits gene therapy studies to somatic cell techniques.

Somatic cell gene therapy works with modified viruses (e.g., adenovirus, adeno-associated virus, lentivirus, retrovirus) that are used as vectors for the delivery of the therapeutic gene product (insertion sites being intravenous, percutaneous, intratumoral, or into the bone marrow), as well as with nonviral transfer technology (e.g., using dendritic cells, ultrasound, stem cells, gene-modified T cells, and, more recently, nanotech robots). Thus, such techniques automatically call attention to ethical concerns about the scientific production of genetically modified organisms (GMOs) and how such recombinant activity should be regulated under the category of “investigational new drugs” (INDs). For example, scientists involved with gene transfer technology using viruses as vectors for gene delivery face unpredictable immune system responses that reduce the efficacy and stability of in vivo gene transfer.

On the other hand, following reports of success with several early-phase clinical trials, despite risks, there is growing interest in the use of gene therapy for neurodegenerative diseases. One of the technical problems with translational trials of gene therapy in humans is the unpredictability of autoimmune responses, in which case any clinical trial in humans has to consider also what “rescue strategy” might be employed. A research protocol lacking this information fails to provide reasonably sufficient information to a human research subject from whom prior, explicit, informed consent is to be obtained, which violates this standard expectation in research ethics involving human participants. That said, however, there is some disagreement among research scientists about how meaningful some animal model studies are in providing relevant data about efficacy in humans. For example, in the case of gene therapy studies that are conducted in primates to study a chronic degenerative disorder such as Parkinson’s, the disease is typically induced in primates by means of a neurotoxin. This creates an analogical disease condition that is nevertheless neither clearly chronic nor degenerative in the primate in the way in which the disease is so for human patients, which therefore raises the question about the relevance of a primate study for a translational trial. However, given the immense risk of experimental interventions involving the human brain, as with research protocol for Parkinson’s, the standard of care is such as to expect morally justifiable translation from in vivo studies only if such research has been conducted in primates in addition to rodents (Kimmelman 2010).

Also, despite transient effect in early gene therapy trials in the case of human immunodeficiency virus (HIV), there is some promise of success in a technique that involves “gene editing” of the coreceptor CCR5 in CD4 T cells. CCR5 is a protein on the surface of leukocytes that enables HIV cell entry and thereby adds to viral load in the HIV-infected patient (Tebas et al. 2014).

Genetic conditions vary widely, including persons with autosomal dominant disorders, X-linked disorders (transmitted by the mother to the son, e.g., muscular dystrophy), and disorders that involve the expansion of a mutation as the condition is passed by an individual to a succeeding generation. These conditions are generally characterized as high risk. Persons having autosomal recessive disorders or carrier status for such disorders have low risk for relatives, given the low probability of added transmissible genetic burden that can occur from marriage to another carrier.

Ethical Dimension

Methods of gene therapy must proceed through various phases of experimentation, involving laboratory studies, animal model studies, and phased clinical trials, prior to a therapy being adopted (“translated”) as part of a standard of care. According to the World Health Organization’s (WHO) international guidelines published in 1997, all such phases of research must also comply with national and international guidelines and regulations that govern such research as a matter of government oversight and public policy. Such research must, of course, account for the basic goals of medical genetics. All biomedical research involves both technical and ethical judgments of medical scientists and the community of peer review. Accordingly, the goals of gene therapy have to account for both (a) the empirical validity of research results (attested to by scientists reproducing research results for validation) and (b) the ethical evaluation of those results with a view to the assessment of individual benefit and risk (in the case of somatic cell gene therapy) and public/generational benefit and risk (in the case of germ-line gene therapy). There is much within the basic science that remains unclear, e.g., the relation of genetic to epigenetic phenomena, in which case there is definite need for caution and more vigorous analysis of risk/benefit when this relationship is part of outcomes assessment. Similarly, outcomes assessment must balance the scientific responsibility of disclosure and dissemination of research results against the confidentiality normally accorded human subjects within specific research protocols. The latter is sometimes constrained by rules of legal liability, depending on the status of legislative developments governing such research.

It goes without saying that genetic conditions affect individuals variously, epidemiological data reported for both industrialized nations and developing countries. In 2006, WHO issued an expert review panel report on the status of medical genetics services in developing countries, which services tend to be limited to genetic testing and screening without research capacity in gene therapeutics. The WHO panel identified several ethical challenges in developing countries as both public and private sector health systems adopt genetics services: distributive justice (access to genetics services), nondiscrimination (relative to genetic conditions), and lack of appropriate safeguards in genetic testing. This set of ethical issues relates to some available epidemiological data, e.g., hereditary conditions accounting for 15–25 % of perinatal and infant mortality and 7.6 million children born with congenital and/or genetic disorders considered to be severe and thus normally requiring requisite medical intervention.

There are significant ethical and regulatory barriers to be overcome in the movement from in vivo animal studies to phased clinical trials of gene therapy products, given the heightened need to assure both safety and efficacy in the use of these products in humans. This is especially important in recent efforts to introduce genetic modification in utero, thus as fetal gene therapy, proof-of-concept studies being done in animal (mouse) models, with adverse events (“vectorinduced oncogenesis,” e.g., high incidence of liver tumors) signaling a need for more attention to ethical concerns about risk/benefit before this technique is moved forward for human trials (Coutelle et al. 2005).

Significant uncertainties are also present in efforts to provide gene therapy for maternally inherited diseases. Mitochondrial disorders due to the problem of heteroplasmy, i.e., the presence of both normal and mutant mitochondrial DNA (mtDNA) in the same individual, tissue, or cell, contrast to the norm where individuals are homoplasmic, i.e., having mostly identical mtDNA and hence functionally normal mitochondria (Poulton et al. 2010). Experimental results in animal models, however, call for caution, especially because there are many unknowns about the relation of mtDNA and a cell’s nucleus and because the alternative use of preimplantation genetic diagnosis (PGD) may provide better predictive information and a more cautious approach to family decision-making in the context of in vitro fertilization (IVF) services.

There have been two prominent uses of gene therapy that caused ethical concern as a result of adverse events: (1) the case of Jesse Gelsinger, who died after being treated for an enzyme deficiency (ornithine transcarbamylase deficiency or OTC) using a modified adenovirus (the virus that causes the common cold) (Wilson 2009), and (2) the case of infants in France treated for X-linked severe combined immune deficiency syndrome (X-linked SCID, also called “bubble-boy” disease). In the latter case, two infants showed an onset of a leukemia-like condition 3 years after gene therapy that was performed by way of retrovirus mediated gene transfer into bone marrow cells (Hacein-Bey-Abina et al. 2003). Consequent to this adverse event, regulatory authorities in France, the USA, and the UK suspended gene therapy trials having similar protocols, with a view to the implementation of additional precautionary procedures.

Bioethics has its place in the clinical setting of medical genetics practice insofar as medical professionals are expected to comply with applicable moral principles as a matter of professional ethics as well as to comply with regulatory guidelines designed to have moral force nationally and internationally. Thus, individual research scientists and medical professionals have a primary responsibility of non-maleficence (“do no unnecessary harm or injury”) even as they have an obligation of beneficence (“do good to the extent of professional ability”), both of which are constrained by patient rights that derive from respect for persons and its corollary recognizing freedom of choice (hence, the criterion of prior, explicit, informed consent to participation in research and consent to recommended treatment in the clinical setting of medical care delivery). The latter are grounded in the moral principle of autonomy (the right of every individual to be self-determining as a matter of every human’s inherent dignity).

The context for application of such principles is not automatic in the way in which someone may apply an algorithm to a problem. In fact, professionals taking such principles into account will necessarily have various attitudes that range across situations of approval, ambiguity, conflicted opinion, and disapproval of alternative actions related to gene therapy. In the context of clinical decision, a clinician’s discretion (and thus “clinical judgment”) remains central to any assessment that engages gene therapy options in relation to specific patient cases. In many such cases, there will be a need to account for new policies governing innovative therapy in relation to extant standards of care in a given area of medical practice.

The regulatory context for medical genetics, including gene therapy, has been articulated in various international declarations, in relation to fast-paced development of the technology, the risk of adverse events associated with novel techniques, and the need to recognize the diversity of cultural beliefs and practices as the sociocultural setting in which clinical practices vary accordingly. These include, for the purpose of international guidance, the Universal Declaration on Bioethics and Human Rights (2005), the Universal Declaration on the Human Genome and Human Rights (1997), the International Declaration on Human Genetic Data (2003), and International Guidelines on Ethical Issues in Medical Genetics (1997).

Of the three primary modalities of gene therapy noted above, it is important to recognize that current prohibitions of germ-line therapy are grounded in concern for the stability of the human genome. The Universal Declaration on the Human Genome and Human Rights (UDHGHR) and other international instruments recognize the genetic diversity of humanity and thus seek to assure, both in applicable principles and regulatory practices, that there is no germ-line modification that derives from “any interpretation of a social or political nature” that would question any individual’s inherent dignity or inalienable rights. This grounding perspective is clear that human dignity “makes it imperative not to reduce individuals to their genetic characteristics and to respect their uniqueness and diversity” (Article 2, UDHGHR). Accordingly, e.g., Article 11 of the UDHGHR prohibits “practices that are contrary to human dignity,” identifying in particular “reproductive cloning of human beings,” which is not now permitted as a matter of public law and policy. This prohibition thus is specific and to be distinguished from permissible gene therapies that “seek to offer relief from suffering and improve the health of individuals and humankind as a whole” (Article 12(b), UDHGHR).

Because of this emphasis on inalienable human rights and both the genetic and cultural diversity of contemporary humanity, there can be no legitimate reduction of human identity to either an individual or a collective sense of the human genome. These are clear normative constraints on any interpretation of “normalcy,” i.e., what counts as a “normal” human being, and these constraints are operative for evaluation that accounts for either genotype or phenotype of given individuals or genetic analysis of given populations.

European nations acting through the Council of Europe adopted the Convention on Human Rights and Biomedicine (1997), with reference to earlier protocol such as the Declaration of Helsinki of the World Medical Association on Ethical Principles for Medical Research Involving Human Subjects (amended, 2000) as well as international guidelines of the Council for International Organizations of Medical Sciences (amended 2002). The European Society for Gene Therapy works to enhance public awareness and recommend on public policy and regulation. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is an organizational effort to join industry and regulatory agencies in the USA, Europe, and Japan for the purpose of drug registration, gene therapy products included.

Many countries have various advisory committees or regulatory agencies concerned with recombinant genetics, these agencies having oversight of gene therapy protocol. In the USA this includes the Biological Response Modifiers Advisory Committee (BRMAC) of the US Food and Drug Administration (FDA) and the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH). For both institutional review processes, protection of patients who become research subjects is the principal concern, given the importance of reducing risk in relation to potential benefit of gene therapy. Here the main criterion in the evaluation of research protocol is to assure human subjects are not exposed to “known unreasonable risks,” results about risks having been gained from in vitro and in vivo research in animal models that are prerequisite to the approval of phased clinical trials.

Isasi et al. (2006) provide an informative overview of regulatory authorities in other countries. These include: the Gene Therapies Research Advisory Panel in Australia, the Gene Therapy Advisory Committee in Britain, the German Commission on Somatic Gene Therapy in Germany (with the German Medical Association having adopted guidelines in 1995 for gene transfer into human body cells), the National Health Medical Research Council in Australia, and the Medical Research Council of Canada.

Both China and Russia have a less rigorous review process, with gene therapeutics in some cases adopted for clinical use without clinical studies (Guo and Xin 2006). In 2006, China did include human gene therapy within its regulations and procedures for new drug evaluation.

In 2004, China became the first country to approve a commercially available gene therapy product, for head and neck squamous cell carcinoma (Pearson et al. 2004). The product (Gendicine) provides a treatment option for head and neck squamous cell cancer patients, China having an annual incidence of 250,000 new such cases.

Despite a diminished regulatory context for gene therapy research in India, some research centers (in Mumbai and Delhi) are conducting gene therapy research in animal models using retroviruses (e.g., for herpes simplex) and murine leukemia virus for transducing hepatocytes (Mulherkar 2010). The Department of Biotechnology of the Ministry of Science and Technology has regulatory oversight of such research, this agency having promulgated ethical policies in June 2001.

Japan continues to make significant advances in the life sciences and biomedical research related to medical genetics and, hence, gene therapy. In 1995, the Ministry of Health, Labor, and Welfare issued its “Guidelines for Clinical Research on Gene Therapy,” attentive therein to “scientific justifiability” in relation to “efficiency and safety” of gene therapy procedures. This was supplemented with another document, “Guidelines for the Assurance of the Quality and Safety of Therapeutic Materials for Gene Therapy,” with the Japan Society of Gene Therapy being formed that year in a move to facilitate and enhance interdisciplinary gene therapy research.

There have been few developments in gene therapy in the African continent. South Africa does have a Medical Research Council, which in 2002 issued its “Guidelines on Ethics for Medical Research: Reproductive Biology and Genetic Research.” The National Health Act of South Africa also regulates human genetic modification technologies, specifically proscribing germ-line techniques.

There have been recent regulatory developments in the European Union, the USA, and the UK. In July 2012, a therapy called Glybera (alipogene tiparvovec) was recommended for approval in the European Union as a treatment for pancreatitis that is due to lipoprotein lipase deficiency (LPLD). In 2013, the FDA’s Center for Biologics Evaluation and Research issued a guidance document for industry for the purpose of assuring adequate preclinical assessment of investigational cellular and gene therapy products prior to their being advanced for clinical trial. In the UK, the government issued proposed regulations in February 2014 that would govern clinical trials using mtDNA gene therapy that produces an embryo with having maternal and paternal nuclear DNA that is combined with mtDNA from a donor oocyte having healthy mitochondria, despite the ethical issues associated with unknown and probable germ-line effects that include advancement of techniques in human eugenics, i.e., the reproduction of human “designer babies” according to parental specifications.

The UK proposal follows an evaluation from the Nuffield Council on Bioethics that recommended in 2012 that such trials may proceed with adequate regulatory oversight, as long as the techniques meet standards of safety and efficacy as treatments and families seeking such therapy are appropriately informed and consenting. These procedures (including here pronuclear transfer and maternal spindle transfer techniques) would be the first trials undertaken in the category of germ-line gene therapy.

By contrast, in the USA, an FDA advisory committee meeting in February 2014 declined to recommend advancing such research from the preclinical stage of investigation in monkey embryos (St. Jean 2014). The FDA’s review – characterized by the FDA as “oocyte modification for the prevention of transmission of mitochondrial disease or treatment of infertility” – is consequent to research conducted at the Oregon Health & Science University, where researchers apparently showed efficacy of the technique in five monkeys and have sought FDA approval for a limited clinical trial.


It is clear that there is a meaningful role for bioethics review in gene therapy as technological developments affect both the clinical dimension of medical genetics and public policy designed to regulate scientific research. Developed nations are much more refined in legislative and regulatory infrastructure than are developing nations, in which case there is ample concern for ethical issues in international biomedical research. That said, the international community of biomedical researchers may benefit from ongoing formulation and revision of international regulatory instruments to assure that both technical and moral judgment are taken into account in research protocols, thus to sustain scientific integrity in this rapidly changing field of scientific endeavor.

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