RISKS INVOLVED IN RETINAL GENE THERAPY – BIOETHICAL CONSIDERATIONS

Jelena Bućan*, Kajo Bućan*

Jelena Bućan, Research Assistant at University Department of Forensic Sciences Split, univ.mag.rel.int. / mag.educ.philol.angl. et ital.

prof. Kajo Bućan, MD, PhD, ophthalmologist, president of Retinal Section of Croatian Ophthalmological Society; regular member Croatian Academy of Medical Sciences, former president of the Croatian Catholic Medical Society – Split branch.

*both authors contributed equally to the final draft of the manuscript

Address for correspondence:

Jelena Bućan

University Department for Forensic Sciences

Address: Ruđera Boškovića 33, 21000 Split

Phone: +385 21 510 180

e-mail: jelena8994@gmail.com

Key words: retinal inherited diseases, gene therapy, bioethics

1. Introduction

Retinal gene therapy could be described as a revolutionary therapeutic approach whose aim is to treat inherited retinal disorders, a group of genetic diseases that can lead to vision loss and blindness. This innovative therapy aims to deliver genes that are missing or defective, directly into the cells of the retina, with the goal of restoring or preventing further vision loss.

The concept of gene therapy for retinal disorders emerged in the late 1980s and early 1990s, with the development of viral vectors capable of delivering genes to specific cells. This led to the first clinical trials in the late 1990s, focusing on Leber’s congenital amaurosis (LCA), a severe form of inherited retinal dystrophy. Since then, the field has witnessed significant progress, with several gene therapies gaining regulatory approval for specific retinal disorders.

Retinal gene therapy has shown promising results in preclinical studies and clinical trials, with some patients experiencing significant improvements in vision. However, it’s crucial to understand that this therapy is not a cure for all retinal disorders. While it holds immense potential, there are inherent risks associated with gene therapy, and its effectiveness can vary depending on the specific genetic mutation, disease severity, and individual patient factors.

2. Discussion

2.1. Ethical considerations in gene therapy

Gene therapy raises significant ethical concerns such as the difference between the ‘good’ and ‘bad’ usage of the technologies, how to distinguish between the characteristics that are considered normal from those which are believed to be a disorder, the concern whether gene therapy’s high cost will possibly limit its availability to the wealthy as well as if human beings should be able to employ gene therapy to improve basic human qualities like height, intelligence, and athletic ability (National Institutes of Health, 2022). On the one hand, the therapy could prevent future generations from dealing with a specific genetic disorder but, on the other, it carries several potential risks, among them being the unpredictability of the development of fetus or other unknown long-term negative effects (National Institutes of Health, 2022). In that sense, it is essential to emphasize the importance of informed consent, ensuring patient autonomy, and addressing potential unintended consequences (National Institutes of Health, 2022).

Furthermore, there are some other ethical considerations in gene editing, encompassing principles such as respect for human dignity, beneficence, non-maleficence, autonomy, and justice (Ethics Centre, n.d.). While respecting autonomy demands informed consent and patient empowerment, beneficence suggests that treatment should benefit the patient. Furthermore, non-maleficence emphasizes reducing possible harm whereas justice requires equitable access to treatment and fair distribution of resources (Beauchamp & Childress, 2019). These principles emphasize the importance of meticulously evaluating the potential advantages and disadvantages, prioritizing patient welfare, and guaranteeing equitable access to treatment.

2.2. Overview of Retinal Disorders Targeted by Gene Therapy

Gene therapy is being intensively researched for a variety of inherited retinal degenerations, which are distinguished by progressive loss of photoreceptor cells in the retina. Inherited retinal diseases (IRDs) are hereditary abnormalities affecting the retina (Cepko & Vandenberghe, 2013). These illnesses can result in visual loss at any age, and there is presently no cure. Gene therapy can effectively treat IRDs caused by single gene mutations. IRDs being researched for gene therapy include Leber’s congenital amaurosis (LCA), retinitis pigmentosa (RP), and choroideremia. (Cepko & Vandenberghe, 2013). When it comes to the mentioned IRDs, studies have suggested that gene therapy can enhance visual acuity and function for some patients (Bainbridge et al., 2015, 2008; Maguire et al., 2008). Clinical investigations indicate that gene therapy can improve visual acuity and quality of life for patients with inherited retinal diseases. In a landmark trial, patients with LCA who received gene therapy reported considerable improvements in their ability to navigate and do daily chores (Bainbridge et al., 2015). Nuzbrokh et al. (2020) found that treating patients with RP resulted in enhanced visual function and reduced disease progression.

While gene therapy is primarily focused on inherited disorders, research is exploring its potential for treating certain acquired retinal diseases, such as: Age-related macular degeneration (AMD) Diabetic retinopathy, Retinopathy of prematurity (ROP). These disorders affect the retina as a result of aging, underlying medical conditions, or other factors.

Age-related macular degeneration (AMD) is the most common cause of visual loss in adults over 50. AMD causes macular degeneration, resulting in impaired vision, blind patches, and difficulty seeing faces. Gene therapy, as a potential treatment for AMD, aims to induce the creation of new blood vessels and protect retina cells from damage (Campochiaro, 2017). While there are no authorized gene therapies for AMD, researchers are exploring gene-based techniques to address the fundamental causes of the complex illness.

Moreover, diabetes retinopathy is a condition that affects the blood vessels of the retina and can cause vision loss by injuring blood vessels, resulting in leakage, edema, and the creation of aberrant blood vessels. Research on gene therapy for diabetic retinopathy shows promise in restoring damaged blood vessels, reducing inflammation, and protecting retinal cells (Barraza-Flores & Pacione, 2020).

2.3. Mechanism of Action in Retinal Gene Therapy

Retinal gene therapy works by delivering therapeutic genes to specific cells in the retina, with the goal of correcting genetic abnormalities that cause various retinal illnesses. This entails inserting a functional copy of the faulty gene or using gene-editing techniques to change an existing gene (Khaparde et al., 2024). The delivery strategy is typically via viral vectors, namely adeno-associated viruses (AAVs), which are engineered to transport the therapeutic gene and safely integrate into the host cell’s genome (Khaparde et al., 2024).

The viral vector is carefully chosen based on its tropism (ability to target certain cells), effectiveness of gene transfer, and safety profile (Khaparde et al., 2024). Following delivery, the vector infects target cells and releases the therapeutic gene. This gene then expresses the encoded protein, which may restore or improve the function of the missing protein implicated in the illness process (Khaparde et al., 2024). In cases of gene editing, the therapeutic gene is intended to directly fix the genetic flaw, resulting in long-term or permanent correction.

Leber congenital amaurosis (LCA) is a group of hereditary (usually autosomal recessive) retinal degenerative diseases. LCA is the second most common group of inherited retinal dystrophies after retinitis pigmentosa with at least 29 genotypes have been identified. In December 2017, the US Food and Drug Administration (FDA) approved the first-ever gene therapy drug for the eye (voretigene neparvovec-rzyl) for the treatment of LCA with a biallelic RPE65 mutation. RPE65 mutation accounts for only 10% of patients with LCA. This gene encodes an enzyme necessary for the formation of retinal photopigment, which is required for vision.  Creating a visual stimulus is a series of enzymatic reactions between the retinal pigment epithelium (RPE) and the neurosensory retina to metabolize dietary vitamin A into 11-cis retinal to generate photopigment. By delivering a functioning copy of the RPE65 gene using AAV vectors, gene therapy hopes to restore normal retinal photopigment production, perhaps restoring vision in people with LCA.

2.4. Potential Benefits of Retinal Gene Therapy

The major goal of retinal gene therapy is to restore or improve eyesight in patients with inherited retinal disorders. By providing functioning genes, gene therapy has the ability to cure the underlying genetic abnormality, resulting in better light sensitivity, visual acuity, and general visual function.

In rare circumstances, retinal gene therapy can reduce or even stop the progression of retinal disorders, thereby preventing additional vision loss and delaying the need for more intrusive therapies like transplantation.  Gene therapy may postpone blindness development and prolong functional eyesight in people with these illnesses. Cai, Conley and Naash (2017) discovered that gene therapy significantly delayed the progression of retinal degeneration in a mouse model of RP. Therefore, gene therapy has the potential to provide long-term or even permanent benefits, potentially eliminating the need for regular or ongoing treatments. Restoring or preserving vision for people with inherited retinal diseases can significantly improve their quality of life. Patients who have lost their sight may struggle with daily duties, social relationships, and overall wellbeing. Gene therapy can improve independence and social integration, allowing for more active participation in life. According to Askou et al. (2019), patients who underwent gene therapy for RP experienced improved quality of life, including increased independence and emotional well-being.

Although the prospective advantages of retinal gene therapy are encouraging, significant bioethical issues must be considered. Informed consent is essential, guaranteeing that patients comprehend the dangers and advantages of treatment, particularly considering the possibility of long-term repercussions. Guaranteeing fair access to this new medication for all patients, irrespective of their socioeconomic status, is essential. Long-term safety concerns, including immunological responses, off-target effects, and unintentional germline changes, must be closely monitored and addressed.

2.5. Risks of Retinal Gene Therapy

The dangers of retinal gene therapy are roughly classified into two categories: those related to the delivery vector and those connected to the therapeutic gene itself. Viruses and other delivery vectors are utilized to convey therapeutic genes into target cells. These vectors can elicit immunological reactions, perhaps resulting in inflammation or rejection of the therapy. Smith et al. (2020) investigated immunological reactivity in patients following retinal gene therapy. Many individuals showed inflammation and immune cell infiltration in the treated area. These reactions were associated with both the viral vector and the therapeutic gene product. Furthermore, there is a risk of insertional mutagenesis, in which the vector enters the host’s DNA in an unexpected position, altering normal gene function or triggering cancer. Jones (2018) examined many incidences of insertional mutagenesis related to gene therapy trials. To reduce the danger of insertional mutagenesis, the study recommends carefully identifying target genes, delivering accurate vectors, and monitoring patients for long-term effects.

The therapeutic gene itself has significant dangers. It may not perform as intended or may possibly have negative consequences. For example, the gene may be expressed at an unsuitable level or in the incorrect cell type. Furthermore, there is risk that the therapeutic gene will not be stably integrated into the genome and may be lost over time which could result in a loss of therapeutic benefit or necessitate additional treatments. Controlling the expression of therapeutic genes once supplied to target cells is a significant difficulty in retinal gene therapy. To obtain the desired therapeutic effect, the gene must be expressed at the appropriate level and duration to avoid negative outcomes. Brown & Chen (2019) investigated ways for controlling gene expression in retinal gene therapy. The study explored the use of promoters, enhancers, and other regulatory elements to optimize gene expression and reduce the danger of overexpression or under expression. The researchers emphasized the importance of choosing promoters with tissue specificity and adequate expression levels in target cells. Gene silencing technologies, including RNA interference (RNAi), can target specific transcripts and control gene expression. They also explored using inducible technologies to control gene expression, allowing for tailored therapy and minimizing off-target consequences (Brown & Chen, 2019).

There are several potential risks associated with retinal gene therapy. These risks include inflammation, immune responses, retinal detachment, and unintended gene integration into the genome (Drag et al., 2023).  When it comes to retinal gene therapy, it is also crucial to stress the importance of careful patient selection, monitoring for potential adverse effects, the need for ongoing research to optimize safety profiles and minimize the risk of complications (Drag et al., 2017).  The latter emphasizes the crucial need for long-term follow-up to assess the long-term safety and efficacy of these therapies.

2.6. Immune System Response Risks

Retinal gene therapy can elicit immune responses that can be harmful to the eye and potentially lead to treatment failure. The delivery vector, such as a viral vector, can trigger the immune system, leading to inflammation, rejection of the therapy, or even blindness.

The introduction of foreign genetic material can trigger an inflammatory response, leading to swelling, redness, and damage to the eye tissue. Also, the body may develop antibodies against the viral vector or the therapeutic gene itself, rendering future treatments ineffective or even harmful. Furthermore, immune cells, such as T-cells, may target and destroy cells that have been genetically modified, leading to loss of therapeutic effect. In order to mitigate these risks, strategies like immunosuppressive therapies, vector modifications, and patient selection are employed.

One major worry with gene therapy is the likelihood of unintended genetic alterations, in which the therapeutic gene integrates into the genome in an unanticipated region. This can result in the disruption of key genes, potentially creating new or worsening health issues. The insertion of the therapeutic gene in the incorrect site may activate or disrupt neighboring genes, resulting in unforeseen outcomes. Researchers and physicians are looking into ways to reduce the danger of unintentional genetic modifications. This includes employing vectors with a lower propensity for random integration, creating more precise gene-editing procedures, and performing extensive genomic analysis before and after therapy.

2.7. Off-Target Effects Risks

Off-target effects occur when the gene therapy vector, intended to deliver the therapeutic gene to specific retinal cells, inadvertently affects other cells or tissues in the body. This can lead to unintended consequences, potentially causing adverse reactions or even long-term health problems. Off-target effects can alter normal gene expression and encourage tumor growth (Schaefer et al., 2016). Miller et al. (2021) investigated the dispersion of viral vectors used in retinal gene therapy. The study discovered that most vectors targeted the retina, although a tiny fraction were also found in other tissues. Therefore, optimizing vector design and delivery strategies can reduce the possibility of undesired tissue transduction.

Moreover, these effects might arise due to the vector’s interaction with other genes or cellular processes, leading to alterations in gene expression or protein production. For instance, if the vector inadvertently targets a gene involved in immune regulation, it could lead to immune dysregulation, resulting in autoimmune disorders or increased susceptibility to infections.

The size, stability, mode of administration, and dispersion of the vector in the eye can all impact the therapy’s effectiveness and safety. Davis and Roberts (2021) investigated various vector delivery strategies in retinal gene therapy. They compared the benefits and drawbacks of several delivery methods, including subretinal injection, intravitreal injection, and gene delivery using nanoparticles. According to Davis and Roberts (2021), viral vectors, particularly AAVs, are the most promising delivery vehicles for retinal gene therapy. AAVs exhibit excellent transduction efficiency, long-term expression, and a favorable safety profile. However, AAVs have limitations such as immunological responses, limited vector capacity, and the risk of off-target consequences (Davis & Roberts, 2021). Researchers suggest using non-viral vectors like lipid and polymeric nanoparticles for improved biocompatibility and lower immunogenicity. Finally, they also reviewed genome editing technologies like CRISPR-Cas9, which have the potential for precise gene changes and targeted therapies (Davis & Roberts, 2021).

2.8. Dose-Dependent Toxicity Risks

Retinal gene therapy, like any other therapeutic intervention, carries the inherent risk of dose-dependent toxicity. This refers to the potential for adverse effects to increase in severity or frequency as the dosage of the therapeutic agent, in this case, the gene vector, is increased. This toxicity can manifest in various ways, ranging from mild side effects to severe complications, potentially jeopardizing the patient’s vision or even overall health.

One key aspect of dose-dependent toxicity is the balance between achieving therapeutic efficacy and minimizing adverse events. While higher doses may lead to more robust gene expression and therapeutic benefits, they also increase the risk of off-target effects, immune responses, and even vector-associated toxicity. This delicate balance necessitates careful dose optimization strategies during clinical trials, involving meticulous monitoring of patient responses and adjusting the dosage accordingly.

The clinical consequences of dose-dependent toxicity can be serious. High doses might lead to visual loss or worsen existing retinal impairment (Trapani et al., 2019). This demands precise dose adjustment and close monitoring during clinical trials. Mitigation measures include employing vectors with decreased immunogenicity, optimizing gene delivery techniques, and controlling transgene expression levels.

Furthermore, the nature and severity of dose-dependent toxicity can vary significantly depending on the specific gene vector employed, the target gene, and the route of administration. For instance, certain viral vectors, particularly adeno-associated viruses (AAVs), have been associated with dose-dependent toxicity, with higher doses increasing the risk of inflammation and immune reactions within the retina. These factors underscore the need for rigorous preclinical studies to assess the safety profile of gene therapy vectors across a range of dosages and to identify potential dose-limiting toxicities.

2.9. Long-Term Safety Concerns

While the initial clinical trials of retinal gene therapy have shown promising results, long-term safety concerns remain a critical area of focus. The potential for unanticipated side effects, especially over extended periods, necessitates ongoing monitoring and research. One concern is the persistence of the therapeutic gene and its potential to induce unforeseen changes in the eye over time. Also, while initial studies have concentrated on short-term outcomes, the long-term impact of gene therapy on the natural course of age-related changes in the eye needs thorough investigation.

Johnson et al. (2023) examined the long-term safety of retinal gene therapy in patients who had received treatment several years prior. The study found that most patients had persistent eyesight improvements, although a small number reported delayed problems such retinal inflammation and scarring. A key concern is the possibility of delayed or chronic immune responses. While initial immune reactions may be minimized by careful vector design and administration, the long-term effects of repeated exposure to the therapeutic gene or its products remain unclear. There is also the possibility of unforeseen interactions between the therapeutic gene and other genes in the eye, leading to unpredictable consequences. The long-term impact of the therapeutic gene on other tissues, especially the nervous system, which is closely interconnected with the eye, is another aspect requiring careful consideration.

Nguyen & Lee (2022) wrote about the ethical dilemmas of conducting clinical trials on retinal gene therapy. They underline the importance of pre-clinical safety assessments, patient-practitioner communication, and follow-up patient monitoring that all enhance the moral conduct of these trials. Informed consent is amongst the most important parts of ethical research and clinical work – it ensures patients understand the risks, the benefits, as well as any other possible treatment options or any other parallel clinical experiments that may be instituted (Macwan et al., 2021). With respect to the retinal gene therapy, informed consent is even more remarkable as technology and its consequences are advancing with time.

Given that patient autonomy is of the utmost importance, it is imperative that individuals are given the ability to make intelligent decisions when it comes to their own healthcare. Such a disposition calls for well-structured and comprehensive explanations regarding the mechanics of gene therapy at a level that the specific patient can easily understand. It is crucial that the information addresses not only the short-term risks and rewards, but the side effects, the likelihood of other diseases, as well as the unpredictability of the treatment’s long-term safety and effectiveness.

Of note here, in this context, is the fact that ethical aspects are wider than the first consent for participation. These are the aspects that touch on the interaction during the clinical trials themselves. Patients have to be informed of new risks and advancements in evidence, which could alter the treatment protocols. Such communication builds strong relationships and ensures that the patient continues to actively participate in decision-making regarding their health.

The ethical issue of equitable means to retinal gene therapy should be a priority by all parties involved as it relates to the wealth or geographical barriers people face. Efforts to rectify the underlying issue will be complex and involve things such as: the need to create new and better pricing strategies for gene therapy that take long term economic health costs into account, getting both private and public insurance agencies to cover it, implement public-private ventures that foster the use of gene therapies in more economically disadvantaged areas, and prioritizing the research for cheaper techniques of manufacturing the therapy as well as improving the delivery methods.

In order to resolve the technology’s high costs of development, manufacture and administration, it will be essential to propose new models that can facilitate so that an imbalance does not arise between those people who have access to the treatment and those who do not.

Additionally, barriers to accessibility are not only financial but also topographic, such as the presence or absence of trained health service providers and specialized medical diagnostics and treatment centers. Eliminating these barriers requires coordinated action on the part of the government, healthcare institutions, and patients’ associations, as well as researchers, in order to make sure that the potential of gene therapy is useful to every person who needs it without taking into consideration their background or circumstances.

2.10. Germline Modifications and Future Generations

Retinal gene therapy brings up significant ethical issues, particularly concerning germline modifications and the question of heritability. While current methods typically focus on somatic cells, there’s always a risk of unintended germline changes. If a therapeutic gene were to integrate into the germline, it could potentially be passed down through generations, altering the genetic makeup of future individuals. The ethical ramifications of such inheritance are intricate and warrant careful consideration.

A primary concern is the possibility of unforeseen effects on future generations. While gene therapy aims to treat diseases, it could also lead to unintended genetic changes that might have harmful consequences for offspring. This raises important questions about the rights of unborn individuals to inherit a genetic makeup that may have been modified without their consent. Informed consent, a fundamental principle of ethical research, becomes particularly challenging when addressing the rights of those who have yet to be born.

Another ethical dilemma arises with the possibility of designer babies. Germline modifications could potentially be used to enhance certain traits, raising concerns about genetic inequality and the risk of social stratification based on preferred genetic attributes. These issues underscore the necessity for strong ethical guidelines and regulatory oversight to prevent the misuse of germline gene therapy for non-medical purposes.

2.11. Disability Rights and Identity

Retinal gene therapy brings up important questions regarding disability rights and identity. While the potential to restore sight is enticing, we must consider how this technology could affect the experiences and identities of those with visual impairments. Some people believe that restoring sight might diminish a part of a person’s identity, especially for those who have lived with blindness or low vision. Conversely, others argue that regaining sight could be empowering, enabling individuals to engage more fully in society. This ethical dilemma requires us to strike a balance between honoring individual autonomy and ensuring that decisions about gene therapy are made with a deep understanding of how it might influence identity and self-image.

Additionally, it’s vital to acknowledge that blindness or low vision can be integral to a person’s cultural and social identity, and changing this aspect of their lives could have significant consequences. Engaging with the disability community is essential to ensure that their views and concerns are considered in the development and implementation of retinal gene therapy. This means providing individuals with visual impairments access to accurate and impartial information about the technology and its potential effects, empowering them to make informed choices about whether to pursue therapy.

3. Conclusion

Retinal gene therapy marks a major advancement in treating both inherited and acquired retinal diseases, with the promise of restoring vision through targeted genetic interventions. While preclinical and clinical studies have shown remarkable results, this therapy also presents various bioethical and safety challenges that require a comprehensive and collaborative approach.

One of the key bioethical issues is ensuring equitable access to the therapy, as its high costs may limit availability to those with greater financial means. Additionally, the long-term safety of gene therapy is still uncertain, considering the risks of immune reactions, unintended genetic changes, and potential dose-dependent toxicity. A particularly delicate ethical issue involves the risk of germline mutations, which could have effects that span generations, as well as the implications of therapy on personal identity and societal views of individuals with disabilities.

Although retinal gene therapy has the potential to revolutionize ophthalmic care, its broader application must be supported by well-regulated protocols, ongoing patient monitoring, and ethically sound clinical guidelines. Future research should aim to enhance the safety profile of the therapy, create accessible funding models, and develop clear bioethical standards to ensure the responsible and equitable use of this groundbreaking technology.

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