Human Gene Therapy

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It may seem undignified to discuss humans in a chapter devoted to genetically modified animals, yet from a purely biological viewpoint, humans are no different than other mammals in regard to science's ability to modify their genetic material. As you know, it is possible to fertilize human eggs with sperm in a laboratory dish and implant the young, dividing embryo into the uterus of the future mother. That mother may or may not be genetically related to the embryo. This technique is called in vitro fertilization, or IVF. This technique is now routinely used to help infertile couples have children.

As we saw, some animals have been engineered with foreign genes, one such gene being the one that codes for a blood-clotting factor. Why not then, one can reason, directly add a functional blood-clotting factor gene to a fertilized human egg that would otherwise become a hemophiliac? At this point, one answer is that this technique would be too dangerous. A point not mentioned previously is that when we insert a foreign gene into an organism, this gene randomly inserts into the genome of the host cell. It does not necessarily replace a copy of that gene in the genome, defective or not. A foreign gene can, by chance, insert into the middle of a gene, effectively mutating it. Thus, the blood-clotting factor gene injected into an egg could insert itself in a place of the genome where it could disrupt other genes. The effect of this disruption would be totally unpredictable; we would not know what gene might be affected and what the effect of the disruption would be on the organism. Another objection that many have is that changing the genetic features of a whole individual will result in genetically altered future generations of this individual. This change in the gametic cells, as compared to change in all the other cells of our body that will not produce future generations, is considered taboo by many.

Human beings can be genetically altered by adding genes to some of the cells of an affected individual rather than manipulating the egg, a procedure that will alter the genes of all the cells in an individual, including the cells destined to be gametes. Thus, gene therapy is being pursued for diseases in which a single gene defect affects primarily one type of tissue whose cells are accessible. In order for the disease to be treatable by this method, we first need to understand which gene is defective. This is an arduous process that we briefly discussed in chapter 9. Once the genetic defect is identified and the normal copy of that gene is isolated, there are two different approaches toward gene therapy. One method is to remove some of the affected cells or cells that will develop into affected cells from the patient, genetically modify those cells, and then return them to the patient. This type of procedure is called ex vivo gene therapy. The second method is to treat the patient directly through DNA injection into his or her organs. This type of procedure is called in vivo gene therapy.

Ex vivo gene therapy is used for diseases that arise from problems with blood or bone marrow cells. These cells, such as our red blood cells and cells of the immune system, circulate in our blood stream.

The very first case of human gene therapy used this ex vivo approach. It was applied to a genetic condition called severe combined immunodeficiency (SCID). This disease results from a mutation in a gene coding for the enzyme adenosine deaminase (ADA). In the absence of ADA, affected individuals cannot develop a functioning immune system and soon die from even minor infections. The first SCID patient treated with gene therapy was a young girl named Ashanti DiSilva. Some of Ashanti DiSilva's T cells (important components of the immune system) were removed from her blood, treated with a correct ADA gene, and reinjected into her body. Today, Ms. DiSilva leads a normal life, over twelve years after her treatment, and her ADA levels are normal. Since this pioneering clinical trial, several additional children with this condition have been treated with gene therapy. However, recently three of the treated children developed the same unusual form of leukemia, a cancer of the blood cells. It seems that all three diseases were caused by the insertion of the corrective gene into or near a cancer-causing gene. This is one danger of gene therapy, and a danger that is unpredictable. Thus gene therapy is still at an experimental stage even for cells that can be easily removed and added back to the patient.

A more general approach to gene therapy is to give a dose of the correct gene directly to the patient. However, this requires a safe vector that can target the gene to the right cells. Recall from chapter 5 that vectors are pieces of DNA that carry foreign DNA into cells. In gene therapy these vectors can be either plasmid or viral and must be able to carry the good copy of the gene to the cells that are affected. Viruses were considered good candidates for vectors for human gene therapy because some viruses, by their very nature, infect only a certain type of cells. For example, the flu virus typically infects cells in our respiratory tract and lungs. Yet an important consideration is that no negative effects be caused by the procedure. This is especially important if the vectors are viral DNA. Indeed, viral vectors must be able to invade the target cells, but they should not cause disease or an allergic response. Because of the potential dangers of viral vectors, some researchers are testing other type of vectors that are not of viral origin to transport DNA into cells.

Viral DNA vectors have already been used in human gene therapy trials aimed at correcting metabolic disorders. One such vector is DNA isolated from adenovirus, a rather benign virus responsible for one form of the common cold. When injected into the liver, for example, this virus is not expected to cause any symptoms. Unfortunately, this is not what happened to Jeff Gelsinger, a patient suffering from a defect in the gene that codes for an enzyme called ornithine transcarbamylase. This enzyme removes ammonia from the blood. The correct version of the gene was cloned into an adenovirus vector and injected into Jeff Gelsinger's main liver artery. Shortly after the treatment, he started showing severe allergic response and died soon after. The autopsy showed that the viral DNA had propagated to all his organs and had triggered a massive immune response that killed him. As a result, clinical trials of human gene therapy using an adenovirus vector have been stopped. However, research continues with other viral vectors, particularly for the treatment of cystic fibrosis, a disease that has major manifestations in the lung cells. Clearly, much work is needed to ensure that gene therapy can be done safely.

Nevertheless, other gene-therapy trials are currently in progress. In the case of hemophilia, for example, one could insert a human blood-clotting factor gene into a viral DNA vector and inject the recombinant virus into the liver of the patient. If this procedure succeeded, the liver cells would make enough of the factor to ensure correct clotting of the blood. The first clinical trials of gene therapy for hemophilia were done on patients who made less than 1 percent of the normal amount of clotting factor. Though initial work was done more to test the safety of the procedure than to see if the disease could be cured, the three patients began to produce normal clotting factor. Though not cured, their symptoms were less severe.

Heart specialists also use gene therapy on a limited scale. It has been shown that the gene coding for vascular endothelial growth factor (VEGF), when injected into human muscle cells promotes the formation of blood vessels. As we know, many heart conditions are due to plugged-up arteries that can no longer supply the heart with oxygen. Injection of the VEGF gene into the heart can alleviate pathological symptoms through the formation of new blood vessels in the heart itself.

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