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Gene therapy

Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, and hereditary diseases in particular. Gene therapy typically aims to supplement a defective mutant allele with a functional one. Although the technology is still in its infancy, it has been used with some success. Antisense therapy is not strictly a form of gene therapy, but is often lumped together with them.


In the 1980s, advances in molecular biology had already enabled human genes to be sequenced and cloned. Scientists looking for a method of easily producing proteins, such as the protein deficient in diabetics insulin, investigated introducing human genes to bacterial DNA. The modified bacteria then produce the corresponding protein, which can be harvested and injected in people who cannot produce it naturally.

Scientists took the logical step of trying to introduce genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia. However, this has been much harder than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering it to the right site on the genome.

Types of gene therapy

In theory it is possible to transform either somatic cells (most cells of the body) or cells of the germline (such as stem cells, sperm and eggs). All gene therapy so far in people has been directed at somatic cells, whereas germline engineering in humans remains only a highly controversial prospect. For the introduced gene to be transmitted normally to offspring, it needs not only to inserted into the cell, but also to be incorporated into the chromosomes by genetic recombination.

Somatic gene therapy can be broadly split in to two categories: ex vivo (where cells are modified outside the body and then transplanted back in again) and in vivo (where genes are changed in cells still in the body.) Recombination-based approaches in vivo are especially uncommon, because for most DNA constructs recombination is a very low probability event.

Ex vivo

The ex vivo approach was the first to be put in to practice. In 1990 trials were run designed to treat children with an inherited immune deficiency, as well as children or adults with high serum cholesterol. Cells were removed from the patients body and incubated with vectors that inserted copies of the genes. Most gene-therapy vectors are viruses, although there are techniques for delivering DNA directly as well. After modification, the cells are transplanted back in to the patient where they will hopefully replicate and produce functional descendants for the life of the transplanted individual.

This technique is best used for diseases where the desired cells can be extracted easily, such as the blood or liver.

In vivo

For in vivo techniques the challenge of inserting the genes is even greater. The vector carriers have a difficult task to complete: they must deliver the genes to enough cells for results to be achieved and they have to remain undetected by the body's immune system.

Much hope has been placed in viruses to deliver the DNA. After all, this is what viruses do naturally insert their genes into cells so that their hosts can reproduce them. Through millions of years of evolution viruses have developed very sophisticated ways of doing this. There are two classes of viruses which look promising retroviruses and adenoviruses.

Retroviruses are small RNA based viruses. Because they reproduce by integrating their RNA into the host's DNA, they carry the prospect of incorporating new genes into chromosomes, so that cells that divide will pass the genes to their progeny. Scientists have removed certain crucial genes from the viral genome, so that they cannot damage the host. RPR Gencell (a French pharmaceutical company) conducted experiments injecting retroviruses into lung cancer patients. After the injections of vectors containing p53 a gene that suppresses tumours directly in to the cancerous tissue, the tumours stopped growing and were broken down by the body.

Adenoviruses are larger, DNA-based viruses, which can carry more genes.

A problem affecting all virus-based vectors is recognition by the immune system. When familiar viruses are detected in the bloodstream the body sends antibodies to bind to and consume them. In retroviral and other recombination-based approaches, a second problem arises in the unpredictablity of where the new DNA inserts into the chromsomes of transfected cells. If the gene is inserted in a bad place for example within the sequence of an important gene, or within non-coding (intron) regions that the cell will never translate to produce protein then the new gene would not be properly expressed and the cell could be made worse or even cancerous.

Scientists are researching an interesting way of bypassing the DNA problems by actually introducing an extra chromosome into the body. Existing alongside existing DNA, this 47th chromosome would contain the genes needed. Introduced into the body as a large vector, it is not expected to be targeted by the immune system because of its construction.

Vectors in gene therapy

Viruses attack their hosts to insert their genetic material into the genetic material of the host. This genetic material contains instructions to produce these viruses. The host cell will carry out these intructions and produce the viruses. This is how viruses spread, in general.

In addition to the instructions producing the components of the virus itself, viruses can carry additional genes containing instructions for creating other kinds of proteins. In theory, if we insert a gene that is missing from a patient in a virus, and infect that patient with the virus, the virus will spread the missing gene in all the cells of the patient. The missing gene is now replaced and the disease is cured. This technique is called gene therapy.

Three types of viruses are currently used as vectors in gene therapy: retroviruses and adenoviruses and adeno-associated viruses. They differ in their mechanisms of action and results.


The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be considered part of the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell, or the chromosomes of the cell. This process is done by another enzyme carried in the virus called integrase.

Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, we can say that the host cell is now modified to contain a new gene. When this host cell divides later, its descendants will all contain the new genes.

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted. If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur.

Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted when leukemia was reported in several of the patients.


Adenoviruses are viruses that carry their genetic material in the form of DNA. When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated into the host cells genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division. So the descendants of that cell will not have the extra gene. This means that treatment with the adenovirus will require regular doses to add the missing gene every time new cells are produced without the gene.

Adeno-associated viruses

Adeno-associated viruses, from the parvovirus family, are small viruses with a genome of single stranded DNA. There are a few disadvantages to using AAV, mainly the small amount of DNA it can carry and the difficulty in producing it. This type of virus is being used, however, because it is non-pathogenic (most people carry this harmless virus). In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus and the cells that have been succesfully treated with it. Several trials with AAV are on-going or in preparation, mainly trying to treat muscle and eye diseases, the two tissues where the virus seems particularly useful.

Problems and ethics

For the safety of gene therapy, the Weismann barrier is fundamental in the current thinking. Soma-to-germline feedback should therefore be impossible. However there are indications that the Weissman b

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