Gene Therapy Up To 2026

Gene therapy is a promising and rapidly evolving field that involves the introduction, alteration, or deletion of genetic material within an individual’s cells to treat or prevent diseases. The primary goal of gene therapy is to correct or replace faulty and defective genes with functional ones, addressing the root cause of genetic disorders and various disease conditions.

There are currently 3000 different conditions that can be attributed to a single gene mutation. On average there are 6 defective genes per person. Most are autosomal recessive and thus of little consequence but about 1 in 10 will develop and experience an inherited genetic disorder once in their lives. Many conditions are caused by multiple gene mutations and really cannot be treated with any form of gene therapy. Typical conditions include diabetes, mental conditions such as Alzheimer’s, hypertension and cardiovascular disease. So, at the moment only monogenic diseases i.e. ones involving a single gene are involved.

At the moment gene therapy is used to treat disease by modifying specific gene expression through gene addition only. It means that there is no preventive used for gene therapy. The original patient’s gene is not removed because a working functional gene is added that is expressed. It is still in its infancy as a technology.

The genetic material that is added is DNA, RNA and oligonucleotides which are short pieces of nucleic acid. A genetic disease can be treated using an added gene that makes a drug usually a protein, say an enzyme that would be missing or defective in the original patient. It may also be a  piece of RNA that is then translated into a protein.

The type of diseases currently treated are genetic diseases which include hereditary or germ line mutations in the patient’s DNA. We also include somatic mutations as in cancer and those conditions which concern acquired deficiency or over-expression of particular proteins. An example would be cytokine imbalances during allergic responses or inflammation.

As a technology it has extraordinary potential. The first approved gene therapy experiment was when Ashanti DeSilva was treated for ADA-SCID on September 14th in 1990. ADA-SCID refers to an enzyme called adenosine deaminase (ADA) which is found in white blood cells (lymphocytes to be more precise) and in some other cells too. It is needed for removing particular types of toxins produced during metabolism. When this critical enzyme is missing, the lymphocytes die and at the least fail to function properly. The situation is responsible for severe combined immunodeficiency (SCID). .

Somatic And Germ Line Gene Therapy

When it comes to classifying gene therapy, one way is to discuss treatment of either somatic cells or germ line cells. In somatic cell gene therapy, the therapeutic genes of interest are transferred into the somatic cells. These include blood cells, skin cells and bone marrow cells. There are many other types but these are enough to be getting on with. At this moment in time, this is the only accepted type of human gene therapy

In germ line cell therapy, the therapeutic genes are transferred into germ cells such as sperm and eggs. On that basis, the genes are then inheritable and can be passed onto later generations. However, the practice is largely banned because there are ethical and indeed safety reasons for conducting such treatment because of eugenics. Experimentally, researchers have for example created different strains of mice with a disease that has then been corrected using germ line gene therapy to demonstrate proof of principle.

In Vivo and Ex Vivo Therapy

In vivo gene therapy requires the direct delivery of the therapeutic genes into cells of a particular tissue in the body such as the liver which is a good target organ. The therapeutic genes are packaged into a delivery vehicle such as a retrovirus and then injected into the patient.

With ex vivo gene therapy, the genes are transferred into cultured cells and then reinserted. In this process, adult stem cells with the genetic defect are removed from the patient and propagated in the lab. The therapeutic gene(s) in this case is inserted into a delivery vehicle such as a retrovirus and then introduced into the adult stem cells. The genetically corrected cells are then selected and grown on. The modified cells are then introduced back into the patient.

In the case of Ashanthi DeSilva who was 4 years old, she suffered with a defective adenosine deaminase (ADA) which was causing Severe Combined Immunodeficiency (SCID). Because there was a genetic defect in the gene coding for ADA, there was no removal of deoxyadensosine which accumulated in T lymphocytes and killed them. If untreated, the immune system is so badly disrupted that the patient dies at an early age from even mild infectious diseases.

In 1992, Dr. Claudio Bordignon performed for the first time a gene therapy study using hematopoietic stem cells as vectors to deliver a range of disease that would correct hereditary diseases. However, not all such therapy works well because there have been deaths from its application.

Germ Line Manipulation

Oocyte Pronucleus Injection or Perivitelline Infection

An egg is injected with DNA using a specialized microscopic guided needle. This pierces the nucleus and the DNA is injected in which theoretically becomes part of the genome. The perivitilline space occurs between the oocyte plasma membrane and the zona pellucida which is just outside the cell itself. When DNA is injected into this area it is taken up and becomes of the nucleus.

The work has never been conducted on human beings but on mice oocytes.

Here are some key aspects of the application of gene therapy in clinical treatments:-

1. Monogenic Disorders:
   • Cystic Fibrosis: Gene therapy has been explored as a potential treatment for cystic fibrosis, a genetic disorder affecting the respiratory and digestive systems. Researchers aim to deliver functional copies of the CFTR gene into the patient’s cells to restore normal function.
   • Hemophilia: Gene therapy has shown promise in treating hemophilia, a blood clotting disorder. By introducing genes responsible for producing clotting factors, researchers aim to reduce or eliminate the need for regular infusions of clotting factor proteins.
2. Cancer Treatment:
   • Immunotherapy: Gene therapy is being used to enhance the immune system’s ability to target and destroy cancer cells. CAR-T cell therapy is a notable example, where a patient’s T cells are genetically modified to express chimeric antigen receptors (CARs) that recognize and attack cancer cells.
   • Tumor Suppressor Genes: In some cases, researchers are exploring the introduction of genes that can suppress tumor growth or enhance the body’s natural defense mechanisms against cancer.
3. Inherited Genetic Disorders:
   • Muscular Dystrophy: Gene therapy is being investigated for various types of muscular dystrophy, aiming to deliver functional genes to muscle cells to restore muscle function.
   • Spinal Muscular Atrophy (SMA): The FDA has approved gene therapy for SMA, where a missing or defective SMN1 gene is replaced with a functional copy to address the underlying cause of the disease.
4. Neurological Disorders:
   • Huntington’s Disease: Researchers are exploring gene therapy approaches to silence or replace the mutated HTT gene responsible for Huntington’s disease.
   • Parkinson’s Disease: The therapy is being investigated to deliver genes that can produce neurotransmitters or neuroprotective factors to alleviate symptoms or slow disease progression.
5. Viral Vector Delivery (Sharon & Kamen, 2017):
   • Adenovirus: One of the first viral vector systems to be developed.
   • Adeno-Associated Viral (AAV) Vectors: AAV vectors are commonly used to deliver therapeutic genes into target cells. They have a good safety profile and are widely used in various gene therapy clinical trials.
   • Lentiviral Vectors: Lentiviruses are used for delivering genes into dividing and non-dividing cells, making them suitable for long-term gene expression.
6. Challenges and Future Directions:
   • Immune Response: The body’s immune response to the viral vectors used in gene therapy can limit the effectiveness of treatment. Ongoing research focuses on developing strategies to mitigate immune reactions.
   • Off-Target Effects: Ensuring precise and targeted gene delivery is crucial to avoid unintended consequences. Advances in gene editing technologies, such as CRISPR-Cas9, aim to improve the specificity of gene therapies.
   • Ethical Considerations: The ethical implications of gene therapy, including issues related to germline editing and the potential for unintended consequences, are subjects of ongoing debate and discussion.

Gene therapy now holds immense promise for treating a wide range of diseases by addressing their underlying genetic causes. While there are challenges and ethical considerations to navigate, ongoing research and technological advancements continue to drive the field forward, offering new hope for patients with genetic and acquired disorders.

References

Sharon, D., Kamen, A. (2017) Advancements in the design and scalable production of viral gene transfer vectors. Biotech. Bioeng. 115 (1) pp. 25-40 (Article) .