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What is Gene Therapy?

Gene therapy is an experimental technique used in treatment of malfunctioning genes, whereby a deficient or defective gene is replaced by a working gene, so that the body can make the proper enzyme or protein and as a result eliminate the origin of the disease.

Gene therapy is therefore targeted to “genetic metabolic diseases” in which a faulty gene causes an enzyme to be either absent or ineffective in catalyzing a particular metabolic reaction effectively.

There are a number of approaches for correcting defective genes:

1. The most common approach is inserting a gene into a non-specific location within the genome, replacing a nonfunctional gene.
2. Through selective reverse mutation, the malformed gene can be repaired to attain its normal role.
3. Via homologous recombination, the normal gene is exchanged for the abnormal gene
4. Alteration of the regulation of a particular gene.⁸

How does Gene Therapy work?

To insert the corrected gene into the patient’s targeted cell, a carrier molecule, called a vector must be used. The most common form of vector is a virus which has been genetically modified to contain human DNA within it. The viruses are modified by replacing the deformed gene with the genes encoding for the desired effect. Thus the virus can be used as a 'vehicle' to carry the good genes into the targeted human cell in a pathogenic manner (see figure 2 below). The target cells are usually a patient’s liver or lung cells, where the viral vector transfers the therapeutic gene into the target cell. The therapeutic gene generates the production of functional proteins and restores the cell to its normal state (see figure 3 below).

Figure 2 - Showing how viruses work 

               www.genetherapy .net

Figure 3 - Showing the process of inserting the vector in gene therapy

 Image Copyright Microsoft Encarta Online Concise Encyclopedia

The types of viruses used in gene therapy

There are six main types of viruses used as vectors in gene therapy (shown in table below):

1. Retroviruses - A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host cells. Human immunodeficiency virus (HIV) is a retrovirus. 

2. Adenoviruses - A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus.  

3. Adeno-associated viruses - A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19. 

4.Herpes simplex viruses - A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen that causes cold sores.¹³

5. Alphaviruses- a single stranded positive sense RNA, particularly used to develop viral vectors for  the Ross-River virus, Sindbis virus, Semliki Forest virus and Venezuelan Equine Encephalitis virus.

6. Vaccina or pox viruses- a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome of approximately 190 kb in length, which encodes for around 250 genes. Can accept as much as 25kb of foreign DNA making it especially useful in expressing a large gene in gene therapy. 

Figure 4- Showing the viruses used as vectors

Non-Viral Options 

The simplest option of non-viral insertion of DNA into the target cells involves direct insertion of the therapeutic cells into the target. This method poses some problems however, due to the large amount of DNA needed and can only be used with specific tissue types.

Another option is of a non-viral approach is the use of therapeutic DNA that chemically links the DNA to a special receptors on the target cells’ molecules. The DNA binds to the receptors, and the cell membrane engulfs the cell DNA and transfers it to the interior of the targeted cell. However the delivery system of this option is not very successful.

A liposome (an artificial lipid sphere with an aqueous core) can also be used to transfer the therapeutic DNA to the target cell through the cell’s membrane.

Challenges in Gene Therapy

Issues with viral vectors- viruses, while the most common choice for a vector in gene therapy, poses several problems. Viruses can trigger immune and inflammatory responses and induce toxicity in the patient. There are also numerous concerns about the viruses ability regain the capability of causing diseases.

The nature of gene therapy is short lived- there are problems with integrating the therapeutic DNA into the patients genome, thereby limiting the long term benefits of gene therapy. Patients therefore have to undergo series of treatment. Before gene therapy can become a permanent cure for a disease the DNA needs to be integrated into genome and remain functional and stable within the target cell.

Immune response-There is always a risk of initiating an immune attack when inserting the therapeutic gene into the patient, since the immune system recognizes the vector as a foreign particle. Additionally, the immune systems enhanced response to invaders it has seen before makes gene therapy difficult to be repeated in the patient.

Mulitigene disorders- Some common diseases, such as Alzheimer’s disease, arthritis and diabetes,  arise from the combined effect of variations and mutations in many genes. Multifactorial disorders are hard to treat with gene therapy since conditions that arise from single mutations are the best contenders for gene therapy.

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