Last update: January 2024
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Definition: What is gene therapy?

Approach: How do somatic gene therapies work?

Gene therapy methods can be used to pursue different goals. The introduction of so-called transgenes into tissues or cells can be aimed directly at correcting or replacing defective or missing gene functions (substitution therapy); this primarily treats monogenetic hereditary diseases, i.e. diseases based on a single gene defect. For the treatment of infectious diseases or cancer, however, gene transfer can also be used to specifically enhance gene functions, for example in the immune system (addition therapy); lastly, gene therapy methods can aim to suppress pathogenic, i.e. disease-causing gene activities (suppression therapy).

The most critical step in gene therapy is the efficient delivery of the desired gene or the tool to repair genes into the right cells. These can either be targeted directly in the organism (in vivo), or cells, for example stem cells from the bone marrow, are extracted and reintroduced into the organism after genetic modification (ex vivo). 

The material to be introduced must be able to survive in the body (e.g. in the bloodstream) long enough to reach the right place without being destroyed straight away by the body's own defense mechanisms. It must also be able to pass through the membrane of the target cells as well as enter the cell nucleus, which contains the genetic material of the cell. This is done using so-called vectors that serve as "ferries" of genetic material. 

Risks

The first studies on gene therapy methods in humans took place in the early 1990s. Gene therapy is therefore considered a relatively young field of research, with only a few clinical studies conducted in comparison to other treatment methods. It is therefore not yet possible to predict the long-term effects of gene therapy treatments. These circumstances represent a risk that can be contained by further intensive research and clinical studies. The following is a brief description of basic risks and difficulties in process development.

In processes in which the genetically modified material is integrated into the genome of the target cell, e.g. with the aid of viral vectors, there is a risk of damaging effects on the DNA (genotoxicity). In so-called insertional mutagenesis, a special form of genotoxicity, the defective integration of the therapeutic gene into the genome can impair the function of intact gene sequences. This may, for instance, affect normal cell growth, which can lead to the development of cancers such as leukemia.

It is also conceivable that infectious gene vectors might be accidentally mobilized or released and could then unintentionally enter the environment, for example through body fluids or when administered to the patient. The transmission or spread can either take place from one person to another (horizontal transmission), or the unwanted mobilization occurs in the organism itself, from somatic cells to cells of the germline (vertical transmission). These risks can be counteracted by developing better vector technology. 

The danger of an immune response of the body to viral or alternative vectors and genetically modified stem and immune cells carries a further risk (immunotoxicity). Immune reactions can range from the elimination of genetically modified cells to organ lesions and severe systemic reactions and are highly context- and disease-dependent. Another barely explored risk in process development is the possible drug interaction when using different vector systems or other active ingredients, which might for instance result in immunological cross-reactions. Determining the correct dose is also difficult, as dose predictions from animal models have limited applicability to humans.

State of research and prospects

Early attempts to treat diseases using gene therapies raised great hopes for future therapeutic options and were accompanied by a veritable euphoria. 1990 saw the first application of gene therapy in humans. A team of researchers from the University of Southern California in Los Angeles successfully treated a four-year-old girl suffering from a genetically caused severe combined immunodeficiency syndrome (SCID).  The reason for the disorder was a defective gene that is actually responsible for the blueprint of the enzyme adenosine deaminase (ADA). Treatment involved the removal of white blood cells from the patient, into which intact ADA genes were then inserted using retroviruses. After the cells were returned to the body, her condition improved significantly. However, the treatment did not completely cure the disease. In addition to the gene therapy, the patients in the study therefore received medication to compensate for the enzyme deficiency. 

The initial euphoria about the advanced therapeutic approaches waned in 1999, when Jesse Gelsinger, then eighteen years old, died during a series of experiments conducted by the University of Pennsylvania. Gelsinger suffered from a congenital disorder of the urea metabolism (ornithine transcarbamylase deficit), which in severe cases can result in death at an early age. He voluntarily participated in the experimental study aimed at correcting the enzyme deficiency responsible for the disease, even though the symptoms of the disease were largely under control in his case. A few days after a high dose of genetically modified adenoviruses was injected into his liver, Gelsinger died of an immune reaction against the viruses.

At about the same time, between 1999 and 2000, a team of scientists at the Hôpital Necker des Enfants Malades in Paris performed gene therapy to treat severe X-linked chromosomal combined immunodeficiency (X-SCID). A total of eleven sick children were treated, ten of whom subsequently developed normal immune defenses. The therapy involved the removal of stem cells from the patients' bone marrow, in which the genetic defect was then corrected by means of gene transfer. The treatment of stem cells initially seemed particularly promising. From 2002, however, it emerged that four of the eleven boys were suffering from unusual leukemias, probably due to the retroviruses used. A similar study, in which leukemia also occurred, was conducted by a British research group at the Institute of Child Health in London. 

In contrast, the study for the treatment of the immune deficiency ADA-SCID, conducted by a team of researchers from the San Raffaele Telethon Institute in Milan, was without leukemia cases. More than twenty children have been treated since the development of this gene therapy in the early 1990s, eighteen of whom have overcome their immunodeficiency, fourteen of whom without further treatment. The therapy was approved in Europe under the name Strimvelis in 2016. It too takes an approach in which stem cells from the bone marrow are genetically modified ex vivo using viral vectors.

Although gene therapy methods as a whole are not yet established therapeutic options, certain gene therapy medicinal products are already on the market. The first authorization of a gene therapy medicinal product worldwide was granted by the European Medicines Agency (EMA) in 2012. Approval was granted for the drug Glybera, which is used to treat the extremely rare metabolic disease lipoprotein lipase deficiency (LPDP). Although almost all patients report an improved quality of life as a result of the treatment, the effectiveness of the therapy is limited because it has not yet resulted in a complete cure. As the production of the drug is not profitable due to the very high costs and low number of potential patients, the manufacturer of the drug UniQure 2017 decided not to renew the European authorization. 

Recently, the focus of media attention was on a study on the treatment of Wiskott-Aldrich syndrome (WAS), which was conducted at Hannover Medical School and the Children's Hospital of the University of Munich. Between 2006 and 2008, a total of nine children suffering from the rare and severe immune deficiency were treated with gene therapy. The therapy initially seemed to be successful, but was then discontinued when the first cases of leukemia occurred after more than two years. By now, eight of the nine children have developed leukemia and three of them have died. The remaining affected children survived the leukemia thanks to a stem cell transplant. The case triggered a heated debate about the application of new therapeutic approaches and their adequate risk-benefit assessment. Critics primarily accuse the leading researcher of having treated sick children with experimental gene therapy, even though they could have been treated with the previously practiced method of allogeneic blood stem cell transplantation. 

The medication Zolgensma, which is used in the treatment of patients with spinal muscular atrophy type 1 (SMA) and has been approved by the EU on July 1st, 2020, received media attention since 2019. This rare genetic disease leads to progressive degeneration of the muscles and is lethal if left untreated. The gene therapy drug Zolgensma promises the survival of the affected person. Once injected by infusion, it has the potential to replace existing lifelong and, ultimately, costly forms of therapy. In the course of so-called "value-based pricing", the pharmaceutical manufacturer Avexis prices the product at almost two million euros, making Zolgensma the most expensive drug currently available. Since 2022, this position has been occupied by Hemgenix, a single-use gene therapy drug for adults suffering from haemophilia B, which has been approved by the US Food and Drug Administration (FDA) and now also by the European Medicines Agency (EMA). The drug was valued at USD 3.5 million per single dose.

Despite the mentioned setbacks, successes in gene therapy research have increased in recent years. Gene therapy is therefore still of great interest as an advanced therapeutic approach. As the cases described illustrate, approaches that serve to correct faulty genes can at present only be used to treat monogenetic diseases. Diseases caused by more complex genetic defects cannot be causally treated with these gene therapy methods. Nevertheless, the researchers' attention is also focused on possible gene therapies for the treatment of various non-monogenetic diseases, especially cancer. However, this involves other approaches to gene therapy. For example, the body's own immune cells can be genetically modified so that they carry artificial receptors on their cell surfaces (CAR T cells) that specifically recognize and attack cancer cells. Experiments with CAR T cells have been carried out for several years now. Promising experiments with CRISPR/Cas9 in cell cultures and animal models also offer hope for the treatment of serious diseases such as AIDS. The first human clinical study with CRISPR/Cas9 for the treatment of cancer, which is expected to provide fundamental insights into the therapeutic potential of the newly developed methods, started in late 2016.

Guidelines of the German Medical Association

As early as 1989, the German Medical Association developed guidelines for gene therapy in humans that assume a strict separation between somatic gene therapy and germline therapy. These state that while the latter was "to be rejected without exception", somatic gene therapy, because its effect is limited to the treated individual, did not raise any significant new ethical and legal problems. The guideline lists a number of conditions which must be met in order for gene therapy, defined "as an extension of existing forms of therapy", to be considered "ethically justifiable". Titled "Guidelines for gene transfer into human somatic cells", a revised and supplemented version was produced in 1995, which was accompanied by the establishment of the Somatic Gene Therapy Commission. The core task of the Commission until 2009 was the technical and substantive assessment of clinical study projects using gene transfer drugs. The introduction of a statutory duty to advise the responsible Ethics Committees for gene transfer studies as required by the twelfth amendment to the German Medicinal Products Act in 2004 was one of the factors that prompted the initial suspension of commission activities and the dissolution of the Commission in 2010, with the simultaneous repeal of the guidelines.

Gene therapy treatments as "clinical trials" and individual "compassionate use”

As the safety risks associated with the development of gene therapy methods are greater than for classical drugs and such methods not only involve considerable scientific interest, but also a high technical and organizational effort, almost all treatments with gene therapy medicinal products have so far been carried out within the framework of "clinical trials" within the meaning of Section 4(23) AMG. In contrast to therapeutically motivated "compassionate use", which is solely aimed at the well-being of the patient, clinical trials are accompanied by a scientific purpose (so-called "therapy studies"). When this stands all by itself, it is called "scientific experiments" or "human experiments". All clinical trials are subject to the requirements of Sections 40 et seq. AMG and Sections 7 et seq. of the German Regulation on the Application of Good Clinical Practice in the Conduct of Clinical Trials with Medicinal Products for Human Use (abbreviated: GCP Ordinance). The mandatory requirements set out here cover a wide range of aspects. For example, objective justification includes that "the foreseeable risks and inconveniences are medically justifiable compared with the benefit for the person on whom the clinical trial is to be conducted (person concerned) and the anticipated significance of the medicinal product for medical science" (see Section 40(1), sentence 3, no. 2, 2a AMG). The informed consent to participation following due information (Section 40(1), sentence 3, no. 3a, b in conjunction with (2), if applicable Sections 40(4)m no. 3, 41(3) no. 2 AMG) as well as the consent to the collection and use of personal data (Section 40(1), sentence 3, no. 3c in conjunction with (2), no. 2a AMG) are subject to subjective legitimation. Finally, the clinical trial is legitimized by a number of conditions applicable to the procedure itself. These include: evaluation by an interdisciplinary ethics committee, proof of a suitable facility and a suitably qualified investigator (Section 40(1), sentence 3, no. 5 AMG) as well as approval and monitoring by the BfArM. The investigators are furthermore obliged to report unexpected incidents immediately (Section 13 GCP Ordinance) and to publish the results "regardless of whether they are favorable or not" (Section 42b AMG). 

Despite the sometimes detailed specifications, the legal assessment is fraught with difficulties and ambiguities. For example, the risk-benefit assessment of gene therapy methods is particularly difficult due to their prognostic unpredictability. Since in cases of doubt individual rights are given greater weight than the prospect of scientific progress, high-risk therapies that may cause unpredictable and serious side effects can at best be justified for the treatment of seriously or fatally ill persons. Accordingly, in its Declaration on Genetic Engineering, the World Medical Association pleads for the strict subordination of gene therapy treatment methods: "If simpler and safer treatment is available, it should be pursued" (Section 7 of the WMA 1987 Declaration). 

The embedding of gene therapy treatments in clinical trials is not mandatory by law. Although both the "Somatic Gene Therapy" Commission of the German Medical Association as well as the Senate Commission on Genetic Research of the German Research Foundation (DFG) have expressed their support for fundamental questions of genetic research against "individual compassionate use" outside of clinical studies, a categorical ban on so-called "uncharted territory therapies" is not prescribed in German law. Compared to standard treatments, however, the requirements for indication, treatment implementation and medical education are significantly stricter for such "novel therapies". In addition, according to a ruling of the Federal Court of Justice in 2006, a new, experimental method of treatment may only be used "if the responsible medical consideration and a comparison of the expected advantages of this method and its foreseeable and presumed disadvantages with the standard treatment, taking into account the well-being of the patient, justifies the use of the new method". This means that the careful selection of the appropriate treatment method in each case is fundamentally subject to medical freedom of therapy. However, according to the same ruling, the attending physician is always obliged to inform the patient about the possibility of unknown risks and to inform him or her about possible dangers. Even if the new treatment method seems to be without alternative from the doctor's point of view, it is still up to the patient to consent or reject the treatment after a comprehensive explanation.

Ban on germline therapy

The targeted artificial modification of human germline cells is strictly prohibited in accordance with Section 5 of the Embryo Protection Act (ESchG). Attempting or conducting germline therapy can be punished with a fine or imprisonment for up to five years. The comments on the Federal Government's draft law on the Embryo Protection Act, which was passed in 1989, state that gene transfer into human germline cells "cannot be justified, at least not according to the current state of knowledge, because of the irreversible consequences of the failures to be expected in the experimental phase - i.e. the most severe malformations or other damage that cannot be ruled out". Furthermore, the risk of misuse, "especially the temptation to use the gene transfer method for the purpose of human breeding", could not be overlooked. However, unintentional changes to the genetic information caused by vaccinations, radiation or chemotherapeutic treatments are not punishable (Section 5(4), no. 3 ESchG). Changes to the genetic information on germ cells are also permitted for research purposes, provided that it is ensured that these are not used for fertilization (Section 5(4), nos. 1, 2 ESchG).

Principles of biomedical ethics  

Against this background, the four principles of biomedical ethics by Tom L. Beauchamp and James F. Childress can be used to identify and structure ethical questions relating to somatic gene therapy. Some of the aspects to be considered with regard to an application to the specific challenges of gene therapy include:

• The principle of autonomy refers in particular to the patient's consent to the intervention on the basis of comprehensive information about the objectives, the implementation, the expected benefits as well as the risks and side effects of the intervention. However, such information is particularly difficult to obtain, especially in the case of advanced therapies such as gene therapy, as it is hardly possible to estimate the expected course of treatment in advance. A problem of legitimacy also arises in the case of patients who are unable to give informed consent in full or in part, or who are underage.
• The principle of beneficence refers to the individual benefit that the intervention brings to the patient. This is evaluated in relation to the severity of the underlying disease to be treated, the theoretical chances of success of the therapy, the availability and benefits of alternative treatments, and the burdens and risks associated with the therapy. An adequate analysis of potential results of gene therapy interventions presents the difficulty of not being able to predict with sufficient accuracy the indirect and direct consequences of the intended intervention.
• The principle of nonmaleficence concerns the assessment and weighing of the risks and burdens of the intervention. It can therefore be seen at first glance as a negative form of the beneficence principle. However, on the basis of an analysis of suffering and risk independent of individual benefit, it is also possible to view the principle of nonmaleficence as an independent principle of action. With regard to gene therapy, the main problem is that the probability and extent of possible harm is almost impossible to determine accurately, given the currently still highly experimental nature of gene therapy.
• The principle of justice concerns the question of the fair distribution of burdens and benefits. Here the needs of several parties are taken into account in order to consider the matter in a supra-individual framework. A central question with regard to gene therapy is whether the acquisition of knowledge with the prospect of future therapeutic use can justify the possibly relatively unfavorable risk-benefit ratio for the patient affected here and now. As most gene therapy approaches to date have been used to treat very rare diseases, the question also arises as to the extent to which it is justifiable, against the background of considerations of justice theory, to employ potentially considerable resources that would only benefit a small number of affected individuals.

One way out of the normative stalemate between principles of equal rank is to prohibit the instrumentalization of persons). This principle requires that a person must never be regarded exclusively as a means to the interests of third parties - be it society, research or other individuals - and must never be used in this sense. Against this background, human studies that focus solely on toxicity may appear ethically problematic in view of the high level of risk and the remaining uncertainty. On the other hand, the prospect of a cure and the simultaneous lack of therapeutic alternatives, such as in the case of compassionate use, can justify gene therapy studies.

Judgment models against the background of a risk-benefit analysis

The current state of public discourse in Germany reveals different ethical judgment models that can be distinguished against the background of a risk-benefit analysis with regard to somatic gene therapy. Michael Fuchs proposes a differentiation of the following four models:

Risk avoidance model
According to this model, an early pursuit of this strategy cannot be justified from an ethical point of view, given the methodological and theoretical uncertainty and the resulting risks associated with the concept and goals of somatic gene therapy. Furthermore, given that somatic gene therapy does not constitute an urgent option in terms of research policy, it is recommended to return to a methodological discussion instead of tying the ethical decision to individual protocol review by ethics committees. Sigrid Graumann, for example, is a representative of this approach.

Drug approval model
The Somatic Gene Therapy Commission of the German Medical Association has proposed that somatic gene therapy should in principle be regarded as a further development of current therapeutic options ("gene-therapy-as-extension view"). Nevertheless, in light of the early stage of development of this approach, it is recommended that the use of gene therapy methods should be limited and initially restricted to patients with serious diseases, particularly those for whom no suitable treatment is currently available and which are often fatal. The proposal focuses on clinical trials, as the development of a therapy appears to be rationally possible only through knowledge gained from its application to a number of patients. However, compassionate use is not recommended.

Staged safety strategy model
The DFG Senate Commission on Fundamental Issues of Genetic Research considers the existing legal framework for gene therapies to be adequate. According to the Commission, gene transfer should be considered an "advanced therapy medicinal product". However, due to the risks of gene therapy methods, viral vectors should only be used in cases of serious disease. Vector systems that do not cause permanent mutations should, after extensive safety tests, also be available for non-life-threatening diseases, as there is no basic differentiation from other pharmaceutical agents in these cases. The Commission is also in favor of banning gene doping and its use in cosmetics where safe vectors are available. Moreover, the experimental application of somatic gene therapy should follow the paradigm of clinical trials.

Controlled compassionate use model
According to the Project Group "Ethics" of the Clinical Research Unit "Stem Cell Transplantation of the DFG", the decision on whether a patient should be included in a gene therapy study should be made individually on the basis of the therapeutic intention and individual prognosis. Although the authors formulate their considerations only in relation to the application of the procedure in Wiskott-Aldrich syndrome (WAS), it can be assumed that their reasoning is also transferable to other gene therapy approaches. Consequently, in view of the uncertain risks involved, progress in medical knowledge can only be of secondary importance to individual benefit. This means that in the case of a grave clinical picture and a lack of alternative treatment options, the possibility of individual compassionate use is advocated.  Furthermore, its use, particularly in the case of patients who are unable to provide consent, must be subject to certain safety standards which should largely correspond to the provisions of the Somatic Gene Therapy Commission.

Comparative assessment of the models

Each of the approaches mentioned contains both sound arguments and certain flaws, thereby provoking critical questions. 

The risk avoidance model takes into account fundamental problems of the concept of gene therapy in view of the setbacks in clinical trials. It is however questionable whether the resulting doubts can withstand the proof of efficacy, as the many published results reporting successful gene therapy treatments of monogenetic diseases should also be taken into account when assessing the efficacy of somatic gene therapies. Moreover, an adequate assessment must also include the theoretical and technical approaches to avoiding undesirable risks.

In contrast, the drug approval model is well established, differentiated and legally equipped with professional elements. Its persuasive power is closely related to the fundamental view of gene therapy as a merely gradual advancement of conventional drug therapies. Yet the analogy between experimental gene therapy and drug approval has conceptual weaknesses that also make the ethical interpretation of the analogy questionable. This applies in particular to a justification of the primary objective of gaining knowledge in view of the known risk and hazard profile and the prohibition of instrumentalization.

The staged safety strategy model contains a complex concept that recognizes the potential risks of a far-reaching new form of therapy, such as gene therapy, and also outlines a strategy for establishing it step by step. However, the question arises as to how the assessment of clinical application should be interpreted in comparison to the overall conclusion of the DFG Senate Commission on Genetic Research. The conclusion includes the recommendation to use gene therapy with retroviral vectors, in the absence of safe viruses, exclusively for diseases without an alternative therapeutic option. Particularly when comparing gene therapy studies using existing vectors and bone marrow transplantation, however, the poor results of donor tissue transplantation are highlighted. This suggests that gene therapy would be the better option, especially for patients for whom no suitable donor is available, despite therapeutic alternatives. However, such an approach would contradict the overall conclusion above.

In the case of the controlled compassionate use model, it needs to be considered whether it is possible to guarantee the high level of scientific and clinical practice required for implementation, as well as control by authorized ethics committees. Although this model focuses on individual patient well-being, it also makes it more difficult to conduct clinical studies. Moreover, it should be examined whether a legitimization of individual compassionate use of this kind would run the risk of creating new gray areas, insofar as the potential individual success could be used as a pretext for a risky experimental procedure.

Suggested citation

German Reference Centre for Ethics in the Life Sciences (2024): In Focus: Somatic Gene Therapy. URL https://www.drze.de/en/research-publications/in-focus/somatic-gene-therapy [date of access]