Gene Therapy – How Does It Work and Its Examples

Gene therapy is a medical therapeutic process involving the delivery of the gene into cells to treat diseases. It is an application of recombinant DNA technology in the field of medicine. The main aim of gene therapy is to cure a disease by providing the patient with a correct copy of the defective gene. The technique can be applied to target specific affected tissues in the body. Although gene therapy was used to treat inherited disease in earlier attempts, the application has now been extended to cure any disease by introduction of a cloned gene into the patient’s cells or tissues instead of drugs. One of the potential benefits of gene therapy is that it can be used to treat diseases with single or few administrations rather than frequent dosing.

The possibility of gene therapy began in the 1960s and 1970s when scientists discovered the first evidence for uptake and expression of exogenous DNA in mammalian cells. However, due to the lack of gene transfer methods and the inefficiency of the techniques available then, the concept could not be materialized. In the early 1970s, the development of genetically marked cell lines and the clarification of mechanisms of cell transformation by the papovaviruses polyoma and SV40 suggested the use of transforming viruses for therapeutic gene transfer. The first attempt to gene transfer in human was carried out by Martin Cline and his colleagues at UCLA in 1980. They conducted an rDNA transfer into the bone marrow cells of two thalassemia patients.

Two Basic Approach To Gene Therapy

There are two basic approaches to gene therapy – Germline Therapy and Somatic Cell Therapy.

Germline Therapy

In germline therapy, germ cells (sperms or eggs) are modified. A fertilized egg is provided with a copy of the correct version of the relevant gene and re-implanted into the mother. If successful, the gene is present and expressed in all cells of the resulting individual. Germline therapy is usually carried out by microinjection of a somatic cell followed by nuclear transfer into an oocyte and theoretically could be used to treat any inherited disease. Germline gene therapy, however, raises various ethical and technical concerns and are prohibited in many countries including Australia, Canada, Germany, Switzerland, and Israel.

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Somatic Cell Therapy

Somatic cell therapy involves manipulation of cells, which either can be removed from the organism, transfected, or then placed back in the body, or transfected in situ without removal. The technique has the most promise for inherited blood diseases such as hemophilia and thalassemia, with genes being introduced into stem cells from the bone marrow, which give rise to all the specialized cell types in the blood. The strategy is to prepare a bone marrow extract containing several billion cells, transfect these with a retrovirus-based vector, and then re-implant the cells. Subsequent replication and differentiation of transfectants leads to the added gene being present in all the mature blood cells. Thus, in somatic cell therapy, the effects caused by the foreign gene is restricted to the individual patient only and is not inherited to the offspring.

How Does Gene Therapy Work?

The gene therapy can be carried out ex vivo or in vivo. In the ex vivo approach, the intended genes are transferred into the cells grown in culture, transformed cells are selected and then re-introduced into the patient. The in vivo approach involves the transfer of cloned genes directly into the tissues of the patient.

The process of gene therapy starts with the selection of a suitable vector, a carrier that will transfer the intended gene to the cells. Two types of vectors used in gene therapy are viral vectors—recombinant viruses, and non-viral vectors—naked DNA or DNA complexes. The viral vectors introduce their genetic material into the host cell and use the host cell’s machinery to produce proteins encoded by the viral DNA. Viruses used in gene therapy are retroviruses, adenoviruses, adeno-associated virus, herpes simplex, and vaccinia. Retroviruses are most commonly used because they can incorporate their genetic material into the host cell’s DNA, thus changing the genetic component of that cell. And they have an extremely high transfection frequency, enabling a large proportion of the stem cells in a bone marrow extract to receive the new gene.

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As the vector binds and enters inside the target cell, its genetic material enters the cell’s nucleus. Then, the viral vector either tricks the host cell’s machinery to replicate its own genetic material or integrate its genetic material into the host genome and cause it to replicate and produce proteins encoded by the viral genetic material. Thus, the therapeutic gene previously recombined with the viral genetic material can be expressed in the host cell.

Gene therapy techniques are applied with various strategies based on the need for function. Gene augmentation therapy is used to add a functioning gene into a cell with a non-functioning copy of that gene. It is suitable to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein. Similarly, Gene inhibition therapy is suitable for the treatment of cancer, infectious and inherited diseases caused by improper gene activity. This does so by blocking the expression of a gene or interfering with the activity of the product of another gene. The third strategy is targeted killing of specific cells such as cancers by inserting suicide gene or genes encoding antigenic proteins. The fourth strategy is correcting a defective or mutant gene to restore its function.

Diseases Treated by Gene Therapy

Scientists and researchers have been working on gene therapy since few decades and hundreds of trials are in clinical phase, most in the first-in-human phase. The number of patients who have received effective gene-based therapy is few but the future of gene therapy is promising. The diseases and disorders that have been successfully treated by gene therapy so far include immune deficiencies—Severe Combined Immune Deficiency (SCID) and Adenosine deaminase (ADA) deficiency, Hereditary blindness, Hemophilia, beta-Thalassemia, Fat metabolism disorder, several types of cancer—melanoma, leukemia, and Parkinson’s disease. Gene therapy is, therefore, becoming the game changer of modern therapeutic medicine.

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