Gene Therapy: Revolutionizing Medicine at the Genetic Level

Gene therapy, a groundbreaking approach in modern medicine, offers the potential to treat and potentially cure a range of diseases by directly addressing their genetic causes. This blog post explores what gene therapy is, how it works, the differences between stable and transient gene therapies, and the basics of gene delivery.

Figure 1. Gene Therapy. Some genes can be non-functional or disease-causing (1). A healthy version of the gene (Therapeutic gene) can replace these (2), leading to a healthy cell with normal function (3)

What is Gene Therapy?

Gene therapy is a medical treatment that changes the genes inside your body’s cells to help fight or prevent diseases. It can be used to replace a non functional or disease-causing gene with a healthy copy, inactivate a disease-causing gene, or introduce a new or modified gene to help treat a condition (1). See Figure 1.

How Does Gene Therapy Work?

Gene therapy works by delivering genetic material into cells, which can then produce the necessary protein to treat a condition. This process typically involves the use of vectors, which are carriers that can deliver therapeutic genes to the patient’s cells. The most common vectors are viruses, which have been modified to carry human DNA (1).

Stable vs. Transient Gene Therapy

Gene therapies can be categorized as either stable (integrative) or transient (non-integrative). See figure 2.

• Stable Gene Therapy: In stable gene therapy, the therapeutic gene is integrated into the patient’s genome. This integration ensures that the gene is maintained within the cells permanently and is passed on during cell division, potentially providing a lifelong cure. However, there are risks, such as insertional mutagenesis, where the integration of the new gene disrupts other important genes (2).

• Transient Gene Therapy: Transient gene therapy involves the delivery of genes that do not integrate into the patient’s genome. The effects of transient gene therapy are temporary, as the therapeutic gene is not maintained in the cells over the long term. This approach is often considered safer but may require repeated treatments (3).
  

Figure 2. Stable and transient gene therapy. In stable gene therapy the therapeutic gene is integrated into the cells own DNA, while this is not the case for transient gene therapy.

Gene Delivery to Cells

Delivering genes to cells is a complex process and can be achieved through various methods:

1. Viral Vectors: Modified viruses, such as adeno-associated viruses (AAVs), adenoviruses or lentiviruses, are commonly used to deliver genes. They are engineered to be safe and efficient at transferring genetic material into cells (4). AAVs can be used for both transient and stable expression of the gene depending on the context and design of the gene therapy, while adenovirus and lentivirus are used for stable expression as they integrate into the genome of the cells.

2. Non-Viral Methods: A commonly used non-viral method for gene delivery is the use of liposomes (fat-based particles) to encapsulate and transfer the gene (5). Other non-viral methods include the use electricity, polymer materials or calcium phosphate to deliver the genes. Non-viral methods are generally safer but less efficient than viral vectors.

Ex Vivo and In Vivo delivery

There are two primary methods for delivery of the therapeutic genes into the body: Ex Vivo and In Vivo delivery. Ex Vivo gene therapy involves taking cells from the patient, modifying them in a lab, and putting them back into the patient's body. This method is particularly useful for diseases where specific cell types can be targeted and allows for precise genetic modification in a controlled environment. On the other hand, in vivo gene therapy delivers therapeutic genes directly into the body using vectors like viruses. This approach is suitable for conditions where extracting and reintroducing cells is impractical, such as with certain neurological disorders or widespread tissue diseases. While in vivo therapy offers the convenience of direct delivery, it faces challenges in ensuring targeted and safe gene transfer to specific cells or tissues. See Figure 3.

Figure 3. Ex Vivo and In Vivo delivery. Ex Vivo gene therapy involves delivering the therapeutic gene to cells isolated from the patient, such as blood cells or stem cells, and then transplanting the genetically modified cells back into the patient. In vivo gene therapy is the direct delivery of the therapeutic gene to an organ or tissue within the body.

Applications of Gene Therapy

Gene therapy has potential applications in treating a variety of genetic disorders, including cystic fibrosis, hemophilia, and sickle cell anemia. It is also being explored in the treatment of cancer, heart disease, and HIV/AIDS (6).

The following are some key gene therapies that have been approved or are in clinical trials:

• Luxturna (voretigene neparvovec): Approved by the FDA in 2017, Luxturna is used to treat patients with an inherited form of vision loss that can result in blindness, caused by mutations in the RPE65 gene.

• Zolgensma (onasemnogene abeparvovec-xioi): This gene therapy was approved by the FDA in 2019 for the treatment of spinal muscular atrophy (SMA) in pediatric patients. It targets the SMN1 gene, which is defective in SMA patients.

• Strimvelis: Approved in Europe in 2016, Strimvelis is a treatment for ADA-SCID, a rare genetic immune system disorder caused by adenosine deaminase deficiency.

• Kymriah (tisagenlecleucel): Approved by the FDA in 2017, Kymriah is a CAR-T cell therapy used to treat certain types of B-cell lymphoma and acute lymphoblastic leukemia.

• Yescarta (axicabtagene ciloleucel): Another CAR-T cell therapy, Yescarta was approved by the FDA in 2017 for the treatment of certain types of non-Hodgkin lymphoma.

• Glybera (alipogene tiparvovec): Although now discontinued, Glybera was the first gene therapy approved in the European Union in 2012 for the treatment of lipoprotein lipase deficiency.

• Spinraza (nusinersen): While not a gene therapy in the traditional sense, Spinraza, approved in 2016, is an antisense oligonucleotide that modifies the splicing of the SMN2 gene, compensating for the defective SMN1 gene in SMA patients.

• Valoctocogene Roxaparvovec (Roctavian): for hemophilia A, this therapy aims to introduce a functional copy of the Factor VIII gene. Approved by FDA in 2023.

• LentiGlobin: In clinical trials for treating sickle cell disease and beta-thalassemia, this therapy involves modifying a patient's own hematopoietic stem cells to produce functional hemoglobin.

• Casgevy: Approved by FDA in 2024. For treatment of beta-thalassemia and sickle cell disease. Casgevy uses CRISPR/Cas9 technology to edit the BCL11A gene in hematopoietic stem cells.
  

It's important to note that the field of gene therapy is rapidly evolving, with new therapies being developed and tested continuously. For the most current information, consulting recent medical literature or databases like ClinicalTrials.gov is recommended.

Challenges and Future Directions

Despite its potential, gene therapy faces several challenges, including ensuring safe and targeted delivery of genes, avoiding immune responses, and achieving long-term efficacy. Ongoing research and clinical trials continue to address these challenges, bringing gene therapy closer to widespread clinical application (7).

Summary

Gene therapy represents a significant advance in the treatment of genetic diseases. By directly addressing the genetic basis of disease, it offers the potential for long-lasting and even curative treatments. As research in this field progresses, gene therapy is poised to become a cornerstone of personalized medicine.

References and further reading

1. History of gene therapy. Gene

2. Gene therapy returns to centre stage. Nature.

3. The once and future gene therapy. Nature Communications.

4. Progress and problems with the use of viral vectors for gene therapy. Nature Reviews Genetics.

5. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proceedings of the National Academy of Sciences.

6. Gene therapy comes of age. Science, 359(6372).

7. Gene therapy. New England Journal of Medicine.