Gene Therapy – Definition, Methods and Applications

What is Gene Therapy?

Gene therapy is an innovative medical approach that involves delivering genetic material into a patient's cells to treat, cure, or prevent disease. The goal is to correct, replace, or silence faulty, missing, or harmful genes. Gene therapy is considered one of the most promising advances in modern medicine, opening up new treatment possibilities for conditions that were previously considered incurable.

Types of Gene Therapy

There are two main approaches to gene therapy:

• Somatic gene therapy: Genetic material is introduced into body (somatic) cells. Changes are not passed on to future generations. This is currently the most widely used and clinically applied form.
• Germline gene therapy: Egg cells, sperm, or early embryos are genetically modified, meaning changes can be inherited by offspring. This approach is banned or strictly regulated in most countries for ethical reasons.

Methods and Vectors

To deliver genetic material into cells, so-called vectors are used. These are carrier molecules or systems that transport the therapeutic gene into the target cell.

Viral Vectors

Viruses are naturally efficient at inserting their genetic material into host cells. In gene therapy, genetically modified viruses from which disease-causing properties have been removed are used. Commonly used viral vectors include:

• Adeno-associated viruses (AAV): Widely used, low immune risk, well-suited for long-term gene expression.
• Retroviruses and lentiviruses: Permanently integrate the gene into the genome of the target cell; suitable for dividing cells.
• Adenoviruses: Suitable for short-term gene expression, but frequently recognized by the immune system.

Non-Viral Vectors

Alternatively, non-viral methods can be used, such as liposomes (lipid-coated carriers), nanoparticles, or direct injection of DNA or mRNA. These methods are often safer but less efficient in terms of gene transfer rates.

CRISPR-Cas9

A particularly revolutionary method is the CRISPR-Cas9 system, a type of molecular scissors that can cut, remove, or modify genes with great precision. This technology has significantly accelerated gene therapy research and is intensively used both in basic research and in clinical trials.

Areas of Application

Gene therapy is being investigated and, in some cases, already clinically applied for a wide range of conditions:

• Inherited diseases: Including haemophilia, sickle cell disease, beta-thalassaemia, Duchenne muscular dystrophy, spinal muscular atrophy (SMA), and cystic fibrosis.
• Cancer (oncology): CAR-T cell therapies, in which immune cells are genetically modified to more effectively target cancer cells.
• Eye diseases: For example, Leber congenital amaurosis, a rare inherited blindness condition for which an approved gene therapy already exists.
• Infectious diseases: Research approaches for treating HIV through genetic modification of immune cells.
• Cardiovascular and metabolic diseases: Mostly still in the research and trial phase.

Approved Gene Therapies

Several gene therapies have already received market authorization, including:

• Zolgensma (onasemnogene abeparvovec): For spinal muscular atrophy (SMA) in young children; considered one of the most expensive medicines in the world.
• Luxturna (voretigene neparvovec): For a rare genetically caused retinal disease (Leber congenital amaurosis).
• Kymriah and Yescarta: CAR-T cell therapies for certain forms of leukaemia and lymphoma.

Risks and Side Effects

Despite significant advances, gene therapy also carries risks:

• Immune reactions: The body may mount an immune response to viral vectors, potentially causing inflammation or allergic reactions.
• Insertional mutagenesis: The random integration of genes into the genome carries a risk of deactivating tumour suppressor genes or activating oncogenes, potentially causing cancer.
• Off-target effects: Genome editing methods such as CRISPR-Cas9 can cause unintended genetic changes at other locations in the genome.
• Incomplete or temporary efficacy: The introduced gene may not always be expressed long-term or in sufficient quantities.

Ethical and Social Considerations

Gene therapy raises important ethical questions. Somatic gene therapy for serious inherited diseases is broadly accepted. Germline therapy, however, is highly controversial, as it would alter the genetic makeup of future generations. International bodies such as the WHO call for strict regulation and transparency in research. Questions of accessibility and affordability are also significant, as gene therapies are currently among the most expensive treatments worldwide.

Future Prospects

Gene therapy is advancing rapidly. With falling costs of genome sequencing, further development of CRISPR technologies, and growing understanding of genetic diseases, it is expected that many more gene therapies will be approved in the coming years and decades. Researchers are working on treatments for hundreds of rare and common conditions.

References

1. Naldini, L. (2015). Gene therapy returns to centre stage. Nature, 526(7573), 351-360. https://doi.org/10.1038/nature15818
2. World Health Organization (WHO): Human Genome Editing - A Framework for Governance (2021). https://www.who.int/publications/i/item/9789240030060
3. European Medicines Agency (EMA): Gene therapy medicinal products. https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products/gene-therapy-medicinal-products