Gene Therapy Side Effects

Introduction

Have you ever wondered about cures for hereditary diseases? Getting down to the root cause of the problem? For many years, around 7,000 rare diseases have affected 10% of the American population, which is only one example!¹ Many researchers have dedicated their lives to pursuing the development of gene therapies for the purpose of reducing this statistic. So, what is the role of gene therapy in this?

Historically, gene therapy has been a concept since 1972, illustrated clearly by Theodore Friedmann and Richard Roblin.² This method of therapy involves the modification of a person’s genes to treat or cure diseases. This can be done through:²

• Replacing a disease-causing gene with a healthy copy of that gene
• Turning off a disease-causing gene that was malfunctioning
• Introducing a new or modified gene into the body to help treat a particular illness or disease

However - like any other therapy - side effects are a concern, and this is especially important because tampering with the wrong genes can have detrimental effects on our health and well-being.

Overview of gene therapy

Types of gene therapy

There are different types of gene therapies, which are summarised below:³

1. Somatic gene therapy: this form of therapy involves changing and modifying a patient’s genes without affecting their germ cells (sperm and egg cells). Hence, changing the patient’s genes will not affect their children and future generations
2. Germline gene therapy: this form of therapy is like somatic gene therapy. However, it deals with changes and modifications in the germ cells or early stages of embryonic development. Hence, these genetic changes will be passed on to the patient’s children and future generations

Mechanisms of gene therapy

To understand gene therapy, we must first address the basics which are the genes. So, what are genes? Genes are the unit of inheritance; they are passed from the previous generation (parents) to the offspring and contain the information required for the physical and biological properties of the offspring.⁴

These genes have various biological codes that produce specific proteins that will contribute to different functions within the body.⁴ However, these genes can also be carriers of disease where certain mutations or abnormal changes to the biological codes can lead to the formation of illness.³

This brings to light the importance of gene therapy and its aim to treat such scenarios, however it is important to keep in mind that gene editing can have unpredictable effects on future generations if the gene therapy is targeted to germline (sperm and egg) cells.³

Gene therapy has several targets, including both cells and tissues:^1,5,6,7,8

1. Muscle cells: muscular dystrophies and other muscle-related disorders can be targeted by delivering therapeutic genes to muscle cells
2. Blood cells: hematopoietic stem cells (blood producing cells) that stay in the bone marrow can be a target for disorders (i.e. certain types of anaemia or immunodeficiency diseases)
3. Retinal cells: the target is cells in the retina, and to treat certain types of inherited blindness or retinal degenerative disorders
4. Central nervous system (CNS): gene therapy is being studied for the treatment of neurodegenerative disorders, such as Parkinson's disease
5. Immune cells (T cells): gene modification of T cells in cancer patients can be performed to enhance their ability to target and destroy cancer cells
6. Bone marrow cells: targeting hematopoietic stem cells in the bone marrow to treat blood disorders, including genetic disorders like thalassemia or sickle cell anaemia
7. Endothelial cells: in cardiovascular gene therapy, endothelial cells lining blood vessels may be targeted to address conditions like atherosclerosis or to promote blood vessel growth (angiogenesis) in ischemic tissues
8. Lung cells: targeting cells within the respiratory system to address conditions like cystic fibrosis

Common side effects

Side effects of gene therapy can be divided into immediate/short-term and long-term side effects.

Immediate and short-term Side effects

Immediate and short-term side effects of gene therapy include^9,10,11:

• Inflammation at the site of injection
• Fever and flu-like symptoms
• Allergic reactions to components of the gene therapy
• Temporary increase in liver enzymes
• Pain and fatigue

Long-term side effects:

When assessing the long-term effects of gene therapy, multiple factors must be considered such as the specific gene therapy approach, the targeted cells and the patient. However, long-term effects are harder to study and require more data and clinical studies. Regardless, some of the long-term side effects include¹²:  

• Off-target effects: there is a potential for gene therapy to affect other genes and cellular functions that are not the target. Hence, posing a risk to the health of the patient
• Immune response: since gene therapy includes the use of vectors and genetic material, an immune response might be triggered in some individuals over time. This can compromise the efficacy of this form of treatment
• Genome instability and integration: studying the stability of the genome post-therapy and the possibility of insertional mutagenesis is a concern in this therapy

Patient-specific considerations

Before commencing gene therapy, the patient’s attributes are important to consider. This includes their age, health status and genetic predisposition:^13,14

• The effects of treatment correlates with the age of the patient
• Pre-existing conditions, previous treatments and any potential contraindications have to be considered to minimise the risk to patients
• Genetics certainly plays a big role in the treatment response; variable gene expression patterns, ethnic diversity and individualised immune response are all factors that affect the success of gene therapy

Case studies

There have been several successful cases of gene therapy demonstrating its potential in treating various genetic disorders. Some of them include^15,16,17:

1. Severe Combined Immunodeficiency (SCID-X1): One of the earliest successful cases of gene therapy involved treating children with X-linked SCID-X1, which is commonly known as "bubble boy" disease. Researchers successfully used gene therapy to correct the genetic mutation causing SCID-X1, restoring the immune function in some patients
2. Haemophilia B: this is a bleeding disorder caused by a deficiency of clotting factor IX. Gene therapy trials have seen success in this area where some patients have experienced significant and sustained increases in clotting factor levels, which reduced the frequency and severity of bleeding episodes
3. Leber Congenital Amaurosis (LCA): is a rare genetic retinal degenerative disorder that leads to severe vision impairment. Successful gene therapy cases were reported, where the addition of a functional copy of the RPE65 gene into the retina resulted in improved vision in some patients

Mitigation and management of side effects

Before therapy is commenced, it is important to perform pre-treatment screening to assess the compatibility of the patient with the chosen therapy. During treatment, the patient should be monitored for any issues and should continue to be monitored after the treatment has been performed to address any side effects that could take place.

However, in cases of side effects occurring, supportive care and anti-inflammatory medications are usually used to treat short-term side effects. In cases of gene therapy affecting the blood cells, blood product support (i.e. transfusions) can be administered to help mitigate the effects.¹⁸

Ethical considerations

When considering a treatment like gene therapy, ethics becomes an issue and a big topic to debate over especially when involving germline therapies. It is important to make sure that the patient is made aware of the details of the procedure as informed consent is crucial. Additionally, this method involves the collection and manipulation of genetic information; hence, it is important to protect the privacy of the individuals. Furthermore, different countries and even cities within the same country can have different values, cultures, and religions, all of which can affect the ethical outlook on gene therapy and its implications.

Therefore, addressing these ethical considerations requires ongoing dialogue and collaboration among scientists, healthcare professionals, policymakers, ethicists and the public. Ethical guidelines, regulatory frameworks and public engagement efforts aim to navigate the complex landscape of gene therapy responsibly and ethically.

Future directions

When thinking about the future of gene therapy, there are several points to keep in mind:^19,20

• Global collaboration and standardisation: where increased collaboration between researchers, clinicians and regulatory bodies can help standardise protocols, ethical guidelines and implement the best practice
• Advancements in vector technology: improvements in viral and non-viral vector technologies (such as nanoparticles) are essential for the enhanced safety and efficiency of gene delivery. Novel vectors with better targeting capabilities, reduced immunogenicity, and improved cargo capacity are being developed
• Gene editing techniques: the development and refinement of gene editing techniques, such as CRISPR-Cas9, are expected to open new possibilities for precise genetic modifications. This may enable the correction of specific mutations associated with various diseases

Summary

In the modern age, technological advancement has seen a rapid improvement, reaching out to molecular and genetic levels. Gene therapy poses as a promising and important tool for therapeutics. However, its side effects are a big concern for the health of potential receivers of gene therapy, including unpredictable immune responses and off-target effects. Hence, it is important that efforts are made to focus on more extensive research in this area to unlock its full potential whilst reducing side effects.