Introduction

Gene therapy is defined as a medical approach that treats or prevents diseases that are life-threatening and lead to a reduced quality of life. It corrects their underlying genetic problem or adds specific features to DNA. Several conditions where gene therapy is used include cancer, spinal muscular atrophy (SMA), duchenne muscular dystrophy (DMD), and sickle cell disease.

Gene therapy is a strategy that corrects the root cause of diseases – the underlying genetic abnormality – rather than managing the diseases’ symptoms.^1,2

In recent years, gene therapy has also been introduced as a method to treat cancer, known as chimeric antigen receptor (CAR-T) cell therapy, offering alternative approaches and new hopes for cancer patients around the world.¹ 

So, what exactly is gene therapy, how does it work, and what are its potential benefits and limitations?

Understanding gene therapy

Genes and DNA

Have you ever heard about the Watson and Crick DNA model? Or maybe the 2020 Chemistry Nobel Prize awarded to Emmanuelle Charpentier and Jennifer Doudna for discovering Cas9 genetic scissors?

These two scientific discoveries are part of the overall achievements since the 1900s that led to the success of therapies based on genetic editing, which is known as gene therapy. 

Before knowing the various targets of gene therapy, we need to understand what a gene is. Genes are hereditary (passed by your parents) DNA codes that instruct all the functions of your cells, including their protein formation. In simple terms, genes determine your eye colour, your blood group, your risk of diseases, if any, and many other characteristics. 

How does gene therapy work?

Diseases are caused by many many factors. Some people have diseases of genetic origins, in which there is a gene abnormality that leads to an abnormal protein or body function. For example, in DMD, genetic abnormality causes a lack of production of a crucial protein, called dystrophin. This leads to changes in the muscle fibres that interfere with the normal muscles’ abilities. Over time, the patient’s disability increases.³ 

Gene therapy aims at fixing this abnormality (or mutations) to restore normal body functions by introducing genetic material that changes how your cells produce proteins. This can be achieved by either:⁴ 

• Reducing levels of certain proteins that cause diseases
• Increasing the production of working proteins
• Producing new or modified proteins within a cell

A brief history

The early to mid-1900s witnessed the development of basic research in understanding genes, DNA structure, and the biological processes involved in causing genetic diseases. By 1972, the concept of gene therapy to treat human diseases was introduced by Theodore Friedmann and Richard Roblin. Since then, milestones in gene therapy continued, leading to success stories of treating incurable and life-threatening diseases.^1,2

Snippets of key milestones

In 1909, genes were discovered, and in 1953, Watson and Crick developed the first DNA double helix model to explain our genetics.

In 2003, gene therapy for oral cancers was first approved in China. 

In 2012, the European Medicines Agency (EMA) approved the first European gene therapy for treating a disease called lipoprotein lipase deficiency. Many therapies, using different techniques, have since been approved throughout the world to treat genetic diseases and different cancer types.^1,2

Using viruses to deliver genetic material to the human body has been the most successful strategy, leading to several medication approvals. Non-viral delivery systems are also currently being explored.⁴

Successful applications

Spinal muscle atrophy

SMA is a rare genetic disease that varies in its severity as per its subtypes. It is the most common fatal inherited disease in early childhood and is characterised by muscle weakness that worsens with time. 

There are four main subtypes, which are defined by the age at which the symptoms started to appear and the disease’s severity. 

Type 0 is the most life-threatening, causing death within the first months of the baby’s life, while type 4 causes mild weakness and has no effect on the patient's survival.⁵ 

Without intervention, toddlers with subtype 1 die before 2 years of age. Until recently, treatment was primarily supportive, like using machines that help with breathing. An approved gene therapy, onasemnogene, is currently available as a treatment option for toddlers under the age of two. In this gene therapy, the normal gene needed to correct the disease is delivered to the body using a virus as a one-in-a-life-time injection.^1,5

Cancer

Multiple myeloma and diffuse large B cell lymphoma are two types of cancer that affect the bone marrow and lymphatic system respectively. When their usual medications do not work, or when these cancers get cured but come back, they are considered severe forms that are difficult to control. In these instances, the cancer is described as having poor prognosis.^6,7

CAR-T cell therapy successfully emerged as a treatment option for these forms of cancer, being approved within the last three years. T cells are a type of immune cell that helps fight cancer and infection. They are edited using viruses to deliver genetic material inside them. 

This edit gives them the ability to become an effective cancer-fighting tool by recognising cancer cells as harmful.¹

CAR-T cells are now one of the most well-known and successful gene therapy applications in immunotherapy.¹

Inherited retinal disease

Medically known as RPE65 mutation-associated retinal dystrophy, this disease affects the photoreceptor cells of the eye's retina. These cells normally take light that enters your eyes and converts it into a form your brain can use for your sense of vision. However, in this genetic disease (a mutation in a gene called RPE65), the photoreceptors do not respond as they should to light and eventually die, leading to reduced vision.⁸ 

Gene therapy, in the form of eye injection, has been authorised since 2017 for the treatment of this renal dystrophy disease. The injection is composed of a virus that delivers the genetic material (normal RPE65 gene) to the photoreceptors of the eye so that they can regain their function.^1,8

Recent developments

Accumulating results from clinical trials and currently approved products demonstrate that the field of gene therapy is promising and advancing faster than ever. Many new genetic therapies are expected to be authorised within the near future. In other words, gene therapy is achieving milestones in treating a broader range of diseases.¹

New editing technologies are further pushing these milestones. CRISPR, a gene editing technology that received the Nobel Prize for chemistry in 2020, and zinc fingers are helping to accelerate the field. In 2023, the first two gene therapies based on the CRISPR editing technology, were authorised to treat two inherited blood diseases.¹

Challenges and considerations

Challenges related to the cost and scale-up of gene therapy production, long-term effectiveness, and safety remain; scientific research is continuously aiming to enhance these aspects.⁹ 

Another important consideration is patient and public knowledge of gene therapies. While regulatory authorities approve and regulate gene therapies, a high level of engagement, awareness, and understanding among patients and the public will ensure they contribute to policy debates. Awareness and education can further inform decisions about trials’ participation (essential for developing new therapies) and routine administration of gene therapies.¹⁰

Current global studies show that patient and public understanding of gene therapies is low. Misconceptions and lack of clarity on various gene therapy topics were noted and have contributed to variations in accepting gene therapies.¹⁰

As a result, patient and public education is needed to accurately provide information to influence their perception and acceptance of gene therapy as an increasingly rigorous method for fighting diseases.¹⁰

FAQs

Is gene therapy legal?

Yes. National regulatory authorities, like the Medicines and Healthcare Products Regulatory Agency (MHRA), Food and Drug Administration (FDA), and EMA, evaluate and supervise the available medications to give authorisation for their use, including gene therapy.

Is gene therapy 100% safe?

Generally, a medication is considered safe when its benefit outweighs its risk. National authorisation for its use will be granted only when these criteria are achieved.

Is gene therapy completely curable?

While enormous progress has been noted in many therapies and scientific research is ameliorating the efficacy of gene therapies, complete curability is not yet achieved.

Summary

Gene therapy is an emerging field that is gaining ground as an option to treat a wide variety of genetic diseases and cancer. With a core concept of introducing genetic material to the cells of the body, gene therapy is providing hope for patients throughout the world who are suffering from incurable diseases, which can be life-threatening. 

The route to optimise this field is still in its early stages. Scientists across the world are gaining new insights and developing techniques to make gene therapy more effective and safe. 

To further help inform decisions in this field, public awareness, and educational campaigns are needed.