Ethical Considerations of Gene Therapy

The biomedical profession's moral and ethical principles surpass boundaries and adhere to the same core concepts: respect for patient's autonomy, beneficence, non-maleficence, and justice¹. Several factors about gene therapy have prompted concerns among scientists, legislators, and the general public. These include the fast progress and accessibility of gene editing, the unknowns with regards to long-term consequences, the danger and impact of unintentional and unplanned gene alterations, as well as purposeful abuse and malicious use of gene-editing technology.

Risk-benefit assessment

Since Hippocrates, "do no harm" has been a basic challenge of the medical profession. Gene therapy is no exception. Finding a therapy for severe diseases should be helpful to the patient, or at least not be any worse than the sickness itself.

Nevertheless, the current knowledge of gene editing is insufficient to predict the medium and long-term consequences of making specific changes in the genome. Furthermore, the impacts of gene editing can last more than one generation since parents pass on their genes to their children. Due to these concerns, gene therapy raises debate among scientists, clinicians and the general public. Some have advocated for a ban on genome-editing technologies in humans, while others believe that the benefits of this technology outweigh the hazards.

Gene therapy criteria

Choosing candidates for gene therapy requires certain criteria to be met. These include:

1. Could the situation be improved by introducing one or two functioning genes?
2. Do we know which genes are at work?
3. Do we comprehend the disorder's biology?
4. Can the gene be delivered to cells in the afflicted tissue?

Somatic gene editing vs germline gene editing

While somatic gene editing is widely regarded as a feasible treatment for severe genetic disorders and cancer, it is widely believed that modified germline cells should not be used for reproduction.

Fig. 1 - Somatic vs germline cells. Only genetic modifications in germline cells are passed down to the next generation

Supporters of germline editing argue that deleting mutations in embryos inheriting a severe genetic condition will reduce the pool of mutations, benefitting humanity overall. This is true for many monogenic disorders, but others are sporadic (occurring in only one family member) or caused by chromosomal rearrangements or de novo mutations that cannot be predicted and hence cannot be rectified.

The risk-benefit analysis is a complex concept that considers factors such as the patient's age, the severity of the disease, the availability of alternative treatment, the psychosocial and economic costs of both performing and not performing the procedure, and yet unknown factors. While the risks of traditional therapies are weighed against the benefits of the patient or group of patients, the assessment of risks and benefits in gene therapy should go beyond the patient since it can affect future generations.

Furthermore, treating a known mutation does not rule out the possibility of another undiscovered mutation being present in a different gene. The targeted mutation may be masking the undiscovered mutation and preventing it from causing any noticeable signs and symptoms. But by treating the targeted mutation, the signs and symptoms of the undiscovered mutation may start to show. Therefore, people treated with gene therapy may show different side effects. This emphasizes the importance of screening for other mutations before starting gene therapy.

We don't know if a mutation that increases the risk of one chronic condition doesn't also protect against another. For instance, a change in the genome of T cells aimed at rendering resistance to HIV was discovered in 2016 to enhance vulnerability to the West Nile virus².

Multifactorial disorders

The situation is much more complex in multifactorial disorders. Since these conditions may be a product of multiple dysfunctional genes or environmental elements, editing a single gene will not be sufficient for effectively treating them. And attempting to alter multiple genes brings on more controversy, since it increases the risks of side effects and unwanted mutations that can have very negative outcomes.

Fig. 2 - Multifactorial disorders are products of genetic and environmental factors

Beneficence in gene-editing therapies

Based on the concept of beneficence, the physician has a duty to care for the patient while minimizing the risks.

Beneficence has multiple levels concerning hereditary conditions:

• Treatment for the patient;
• Treatment or prevention for other family members;
• Relief or delaying of severe symptoms for which no cure is available

When the sickness is severe, and there are not any traditional treatments that can cure or improve the symptoms, it is quite likely that a well-designed gene-editing therapy would be seen as more useful and preferable than traditional medications or the disease's natural progression.

On the other hand, using gene therapy for a flaw, such as colour blindness, which has limited effects on quality of life and allows for a reasonably normal lifetime, can have a significantly greater risk to benefit ratio, making the treatment not endorsed unless the risks are less than minimum. This is why a higher risk associated with gene-editing treatment must be evaluated against the likelihood of the illness being mild.

If the genetic condition affects several organs and systems, it is critical to collaborate in a multidisciplinary team to provide the patient and family with the finest care possible. This is particularly true for long-term follow-up after gene therapy when the physician is seeking indications of off-target or harmful consequences in addition to monitoring the progression of the primary illness.

Autonomy and informed consent

Involving the patient in the decision-making process about their diagnosis and treatment plan, which can take into consideration the health-related advantages and their beliefs and cultural values, is an essential aspect of medical care. A realistic approach would be to present the patient with a thorough and clear description of the issues, potential therapies, and recommendations, allowing them to make an informed decision.

Regarding reproductive options and prenatal gene therapy, the family, and ultimately the mother, must make the decision.³

Genetic information can be difficult to understand for the public or even some members of the healthcare team, which is why it should be presented by a geneticist, a genetic counsellor, or another person trained in genetics to ensure that the patient correctly understands the therapeutic intervention.

A patient with an untreatable serious disease may perceive any therapy as preferable, and not properly evaluate the risks. However, the hazards, potential remedies, reversibility, or alternatives should be clearly highlighted.

In the case of somatic gene-editing therapy for cancer, for example, traditional methods (chemoradiotherapy) can be presented as an option; in embryo editing for the prevention of a genetic disease that runs in the family, in vitro fertilization and preimplantation genetic diagnosis can be offered to select healthy embryos for implantation.

Eugenics and genetic enhancement

One of the primary concerns about genome editing in gene therapy is the possibility of it being utilized for non-medical goals, such as augmentation or eugenic activities.

Human enhancement is most commonly associated with the genetic engineering of humans, which involves changing genetic material to create a selection advantage such as immune protection, height, muscle mass, intelligence, etc. Advanced understanding in genomics and genome editing has reignited the debate over human improvement and the ability to pick the traits of our offspring in the same way that we choose clothes in a store.

"Designer babies" is a commonly used phrase to describe human beings whose genes have been deliberately edited to offer particular qualities, such as the colour of their eyes, hair, or skin, based on their parents' preferences.

Can selecting an embryo for in-vitro fertilization (IVF) from a pool of other embryos with various genetic features be described as eugenics? What about terminating a pregnancy with an afflicted embryo? Or do the family have a right to have a healthy child and express reproductive autonomy? These issues are controversial.

Some argue that a family's decision to pick a healthy embryo and eliminate one with a harmful genetic mutation is not eugenics because it is restricted to an individual or a family and will not impact a broader population. However, the patient's or their family's choice may be influenced by the availability of medical treatment and societal restraints.⁴

We know very little about what genes cause us to be smarter, taller, or stronger; all of these are multifactorial characteristics that come from the combination of our genome and environment. If we attempted to tweak our DNA to enhance its qualities, we would have to make several modifications at once without correctly predicting the effect.

There is a widespread agreement in the scientific community that germline editing, particularly non-medical uses, should be prohibited and that a major public consultation should take place before any application is launched. When genome editing is approved to be utilized for therapy, a suitable supervision structure should be in place to avoid it from being misused.^5,6

First Name Second Name, Full title, Journal, Date

2. Beth Baker, The Ethics of Changing the Human Genome, BioScience, 2016

3. S. Hostiuc, ed., Clinical Ethics at the Crossroads of Genetic and Reproductive Technologies, 2018

4. C.J. Epstein, Is modern genetics the new eugenics? Genet Med. 2003

5. Beth Baker, The Ethics of Changing the Human Genome, BioScience, 2016

6. J.H. Wang, R. Wang, et al., Public attitudes toward gene therapy in China, Molecular Therapy-Methods & Clinical Development, 2017