DMEJ

   Duke Medical Ethics Journal   

Ethical Pathways to Clinical Implementation of Gene Therapy

By: Makayla Gorski

I. Introduction

In 1990, the first gene therapy trial on humans was conducted by NIH researchers. This enabled the modern reality of a projected ten to twenty gene therapy FDA approvals per year by 2025 and with a compounded annual growth rate of the gene therapy market at over 20% until 2028 [1-3]. In short, the clock is ticking for ethicists, scientists, and science policy makers; gene therapies are nearing clinical platforms and are at the forefront of medical solutions for those suffering from genetic disease. As the science behind gene therapy continues to make significant advances and come into use, regulatory and ethical frameworks must be equipped for the associated challenges of gene therapy’s new era. 

Gene therapy is defined as a medical intervention containing recombinant nucleic acids that alter one’s genetic sequence with therapeutic intent [4]. Therapy to treat or prevent genetic disease is commonly achieved with the use of a viral vector to replace, eliminate, or introduce a certain genetic sequence within the genome. Prior to approval for wide use, gene therapies are tested in vitro and in animal models [5]. In contrast to germline gene therapy, somatic gene therapy is non-inheritable and can be administered ex vivo, in which modified patient cells are reinserted, or in vivo, in which therapy is directly provided to the patient [6].

"In short, the clock is ticking for ethicists, scientists, and science policy makers; gene therapies are nearing clinical platforms and are at the forefront of medical solutions for those suffering from genetic disease"

When evaluating the ethics of gene therapy—as well as other forms of precision medicine—in a more general context, there are three distinctions that must be made. First, is the therapy in question being applied in a research context or as a clinical intervention? This distinction targets ethical issues such as accessibility of the treatment, the potential for obsolescence of particular genetic traits, associated health risks, and the practice of ethics dumping. Relevant evaluations to be made include who has access to the therapy, whether the therapy has potential to drastically alter the genetic composition of society, whether the therapy will put the health of patients or research subjects at risk, and whether evasion of regulations in one’s native country places an unfair burden on the country the therapy is administered in (known as ethics dumping). In regards to developing an ethical pathway for gene therapies to reach clinical platforms, ethics dumpling is one important consideration for policy makers. By locating unethical studies and clinical trials elsewhere, the countries with stricter regulations lose economic, instrumental, and intellectual value [7]. Also of importance to policy makers when considering the scope of gene therapy regulations is the unfair allocation of the study’s burdens on subjects of the research in countries like India that relaxed research ethics legislation in an attempt to compete in the global pharmaceutical market [8]. While accessibility and obsolescence are ethical issues that may be more pertinent in the next few decades, the associated health risks and the practice of ethics dumping are of concern now—especially as preclinical gene therapy research is underway around the globe. The current consensus among the modern scientific community is that the study of gene therapy is more ethically permissible than use of gene therapies in a clinical setting. However, as advancements in the relevant science pushes the boundaries of the present ethical standards, shared concerns across countries call for an international conversation, not necessarily a consensus.

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Second, is the therapy targeting somatic or germline cells? While somatic gene therapies only target a portion of an individual’s cells, perhaps limited to a single type tissue, edits to germline cells alter the genetic information in all of an individual’s cells. With germline gene therapy, the new or altered genes are passed down to the individual’s children, and their children’s children, and so on. The potential for altering the genetic information of future generations is of the most contentious issues concerning gene therapy. This second distinction focuses on ethical issues such as designer babies, the rights of unborn individuals, and the potential for mosaicism as well as off-target impacts—all of which are incredibly complex subject matters. The current consensus among the international scientific community is that it is ethical to use and study somatic gene therapy, but not germline gene therapy [9]. While a review of relevant ethical considerations and challenges of gene therapy’s clinical implementation will not address germline gene therapies, as they are not currently approved for clinical use, these issues may one day be relevant if germline gene therapies become acceptable for clinical use. 

Third, does the therapy have cosmetic or therapeutic intent? This third distinction targets ethical issues such as the potential for enhancement and, once again, accessibility. Enhancement is defined by Human Genome Editing: Science, Ethics, and Governance as “changes that alter what is ‘normal.’ ” Today, of considerable contention is refining the distinction between what constitutes medical and nonmedical applications of therapy [10]. The current international ethical standard is that medical application of gene therapy and the prioritization of advancing medical gene therapies (over nonmedial gene therapies) to the clinical setting are most acceptable. However, this standard is difficult to adhere to in cases where the medical-nonmedical distinction cannot be clearly made. For instance, if a somatic gene therapy is clinically available and targets the epithelial cells of burn victims to improve skin elasticity and microbial function, is this a cosmetic or therapeutic application? Overall, knowledge of the current hierarchy of ethical evaluations and current international standards will be of utmost importance over the course of this century. 

II. Accessibility

Accessibility is an important ethical consideration in terms of what populations will have access to therapies in the clinical setting and whether widespread availability of gene therapies would limit the accessibility of interventions to those suffering from genetic disease. The same science that treats those suffering from Duchenne muscular dystrophy, skeletal dysplasia, dystrophic epidermolysis bullosa, and progeria has implications for enhancing muscle mass, height, skin elasticity, and anti-aging capabilities in healthy individuals. For therapies with enhancement applications, concerns arise that advances in technology may render the availability of therapies to those suffering genetic disease inaccessible [11]. The current consensus among the general public, scientists, and regulatory agencies such as the World Anti-Doping Agency (WADA) is that somatic gene therapy studies with the primary purpose of treating those with genetic disease are acceptable. From the late 20th century to modern day, polling continually indicates a sharp contrast between the approval of gene therapy for medical purposes as opposed to approval of nonmedical enhancement [12, 13-15]. In the two decades since the first gene therapy trial, gene doping, or the practice of using gene therapy for boosted athletic performance, was the first enhancement application to come to fruition [16]. Lee Sweeney’s 1998 study with the intended application of improving muscle mass of those suffering from muscular dystrophy earned him popularity among American football coaches and Olympic athletes hoping to bring such therapies to the clinical platform for competitors [11]. Fortunately, continued scientific advancements inform regulatory agencies of methods to act on the collective aversion to nonmedical gene therapies and limit accessibility of clinical trials only to those suffering from genetic disease. For example, gene doping previously detectable only through muscle tissue biopsies is now identifiable with blood samples, aiding implementation of WADA and FDA regulations [17-19]. Still, with the potential use of gene therapy on healthy “patients”, accessibility remains an issue in relation to equity. 

Accessibility is also an important ethical consideration in regards to affordability and safety for groups who were underrepresented in clinical trials. For example, in the case of genetic blindness and visual impairment, a pricey, FDA approved gene therapy does exist, known as Luxturna. For a one time treatment of Luxturna, a gene therapy patient must pay a hefty sum of $850,000 [20]. For a low to middle-income individual suffering from inherited blindness, this gene therapy is not just inaccessible—it is out of the question. Additionally, accessibility is also imperative in regard to demographic representation. If clinical trials required to advance gene therapy drugs to the clinically approved status fail to include underrepresented and vulnerable research subjects, are the gene therapies truly accessible and safe for all? In order for gene therapy drugs to proceed ethically to the clinical implementation, representation and justice must be priorities in every step of the way, especially in the testing stages. The wide array of research subjects who bear the burden of clinical trials should have access to the benefits of gene therapy research. 

III. Obsolescence

Although there is support for enhancement-based gene therapy among philosophers as a mechanism to “reduce inequality”, arguments against somatic gene therapy are posed by bioethicists and the general population on the grounds of obsolescence. As therapies capable of eliminating traits associated with disease are put into practice, the continued potential for such traits to become obsolete arises [21, 22]. Discrimination on the basis of what traits an individual possesses and the obsolescene of traits in older populations in comparison to younger generations threaten to overturn existing social norms and ethical frameworks. In the case of genetic deafness, for example, some individuals may not wish to be “fixed” should a relevant gene therapy become clinically available and other deaf communities may not want hearing impairment to become an obsolete trait. In terms of obsolescence, even more important as an ethical consideration is the widespread use of medical somatic gene therapies leading to the obsolescence of disease as a vector to regulate population growth. Surveys of populations in the United States, Canada, and China indicate that the decreased incidence of disease and subsequent defiance of “the laws of nature on human life and death” is an ethical issue of importance to participants, with one study citing “going against nature” as one of the top five concerns of those surveyed [14, 23]. Thus, despite the philosophical support for somatic gene therapies, evidence indicates a consensus between bioethicists and the general population as to the threat obsolescence—of certain traits and of disease—that is propagated by increased availability of gene therapies. 

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"Therefore, leniency in research regulations in order to reap proportionately greater health benefits for those suffering from genetic disease may also allow negligence of safety among companies advertising enhancement gene therapies"

IV . Associated Health Risks 

Evaluation of the ethics of somatic gene therapy in the clinical setting involves consideration of safety and efficacy. Though of highest concern to those undergoing the respective therapy, health risks are of importance to regulatory agencies, medical providers, and pharmaceutical companies manufacturing gene therapy drugs [24]. Potential harms of somatic therapies fall into two categories: risks demonstrated through previous somatic gene therapy studies—including insertional mutagenesis, mosaicism, and immune reactions to viral vectors—as well as unperceived risks that could develop decades after a gene therapy is administered [25]. Perception of the threat of medical side effects varies greatly among individuals of different countries and education levels. A majority of public opinion polls indicate that the potential of developing side effects or cancer is of utmost concern in comparison to other ethical issues such as accessibility [14, 26-28]. At the same time, participants asked to consider a cost-benefit analysis of risks, rather than rank each ethical concern in relation to others, cite health risks as less of a concern. For example, in a Biotech survey conducted in Germany, only 33% of participants polled felt the associated medical risks of gene therapy outweighed the potential health benefits [29]. The contrast of perception of risks between countries may stem from the greater trust German citizens have in their medical providers, rather than from individual ethical beliefs. For individuals with a strong belief that their medical providers would do no harm and who have the educational context of gene therapy’s  ability to lessen the impact of genetic disease—as opposed to other medical interventions—clinical use of gene therapies is ethically permissible. However, the safer therapies become for clinical use, the more open the application is to enhancement purposes. While the safety of gene therapy for treating disease is of highest concern to medical providers and pharmaceutical companies, commercial biotechnology companies often undervalue safety when considering the intersection of these gene therapies with potential enhancement applications. The CEO of Bioviva, Elizabeth Parrish, was the first volunteer to undergo anti-aging gene therapy, thus a stakeholder in the current approval process of gene therapies for clinical use. Citing instances in which the FDA redacted previously approved drugs, she claims in her 2016 open letter that “a perfectly safe technology has never been created” and emphasizes the necessity of commercial therapies as a mechanism to understand disease, rather than the contrary [30]. Therefore, leniency in research regulations in order to reap proportionately greater health benefits for those suffering from genetic disease may also allow negligence of safety among companies advertising enhancement gene therapies. 

V. Proposed Pathways to Compliance with Current Ethical Standards and Conclusion 

First, regulating research practices and clinical trials of somatic gene therapies, especially those with enhancement implications, tackles compliance with ethical standards at its root. Thus, developing a balance in categorizing gene therapies as those with the primary purpose of treating or curing disease—that can be regulated in application—and those with non-medical applications—that can be regulated initially in study authorization—enable efficiency and efficacy of ethical regulations. At this time, research studies and gene therapies used for enhancements in humans are not ethically permissible and should not secure approval through IRB and ethical frameworks. For medical somatic gene therapies that have nonmedical implications, regulation at the applicatory level, such as of the dissemination of the relevant research and clinical trials, will appropriately assure ethical compliance while avoiding unnecessary burdens on researchers working in a critical timeline to aid patients suffering from genetic disease. On this same basis, the interests and inclusion of only individuals suffering from genetic disease should be the fundamental consideration of ethical frameworks over those with only the desire of enhancement. However, establishing the standard to categorize therapies into these categories involves a more standardized definition of disease [31]. Since there exists an international discrepancy in what constitutes medical application of therapies and in what ethical issues are of greatest concern, categorization of gene therapies must be developed on a national basis. Second, the issue of evasion, or ethics dumping, calls for an international minimum of regulation [32]. This would avoid unethical burdens on less regulated countries and prevent ethical negligence on the part of private biotechnology companies conducting studies incentivized by profit. Third, adaptability of existing ethical frameworks and policy should accommodate accelerations in the advancement of science, so as to monitor enhancement and germline applications of research as they are realized. This can be accomplished through expanding the revisional capacities of institutional review boards when gene therapies are in clinical trials. Alternatively, adaptive protocol could arise from more frequent use of review boards like the National Institutes of Health's Recombinant DNA Advisory Committee as forums to mediate discussion among regulatory agencies with insight from relative stakeholders [33].  Together, more adaptive regulation of somatic gene therapies, with additional categorization of therapeutic intent and international consensus, ensures accommodation of ethical considerations, such as health risks, accessibility, and obsolescence, as science evolves.

Review Editor: Sophie Cary
Design Editor: Harris Upchurch
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