Gene Therapy: Where are we today?

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Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: February 22, 2004

What is gene therapy?

Genes are specific sequences of DNA that serve as the fundamental units of inheritance. Sequences of DNA encode for specific proteins, which in turn perform most of the necessary functions of life. When genes are altered or damaged, the proteins for which they encode are also altered and become unable to perform their normal, physiologic functions. The result is a genetic disease. Gene therapy is a tool that was developed in an attempt to treat genetic diseases by correcting the underlying defective gene itself. Gene therapy has several approaches: (1) a normal gene may be inserted to replace the role of the malfunctioning one, (2) a normal gene may be physically exchanged for the nonfunctioning gene, (3) the malfunctioning gene could be repaired, (4) or the regulation of the gene in question may be modified.

How can we replace the "abnormal" gene with a "normal" one?

In order to insert DNA material into human cells a carrier, also called a vector, must be used. The most commonly used vectors are viruses. Viruses, unlike bacteria, are not self-sufficient. Viruses consist only of either DNA or RNA that is surrounded by a protein coat. They lack the machinery to obtain energy (food and water) and cannot replicate on their own. In order to survive, viruses must live inside autonomous, living cells. Once a virus enters a cell, it integrates its own DNA with that of the host cell. Viruses rely exclusively on the host cell machinery for nourishment, replication and function. Once the viral genome becomes part of the host cell's genome, it will be passed on to each daughter cell with every cell division. This is how viruses are able to infect so many cells very quickly.

Researches have tried to capitalize on this special property of viruses by manipulating the viral genome and then allowing the virus to infect certain cells. Because viral DNA is much smaller and simpler than a human cell DNA, scientists are able to manipulate it much more easily. Researchers have successfully placed "therapeutic DNA" material into a virus and then used this virus to infect a diseased cell. For example, imagine a patient who suffers from a genetic disease caused by lack of production of a single crucial protein. (Cystic fibrosis and sickle cell anemia are two examples of such diseases). In the laboratory, scientists can synthesize a strand of DNA that codes for the missing protein and place this strand inside the viral protein coat. The engineered virus would then be allowed to infect the patient. Once inside a cell, all of the viral DNA will integrate itself with the genome of the host cell. The cell is unable to recognize which DNA is native and which is viral and therefore accepts the genome in its entirety. Furthermore, since the genome is not recognized as being foreign, the cell will begin to produce the deficient protein encoded by the newly integrated DNA. The elegance of this technique is that only one strand of therapeutic DNA is required to remedy the problem. With each cell division the host cell will pass on a copy of this one DNA sequence to each of its daughter cells.

What are the potential complications of this?

The problem is that viruses can and do infect more than one cell type. Thus, when a virus is used as a carrier it can infect more than just the intended cell. It is not always evident what the virus may do to healthy cells that may be infected in the process. Even if this were not as issue, there is still little guarantee that the gene the virus carries will be inserted in the correct location with in the cells genome. If it is inserted in the wrong location, there is a potential that it would damage adjacent healthy genes leading to other problems or abnormalities. Some scientists worry that there is a possibility that the therapeutic gene would be overexpressed. Meaning that the protein for which the gene encodes would be produced in too large a quantity. The consequences of protein overproduction are not clear and this in itself may sometimes promote cancer.

Can we do this without viruses?

There are non-viral vectors that have been developed. One such technique requires directly placing the therapeutic DNA into the target cell. This approach is very limited, however, because some target cells are not readily accessible, Furthermore, because the therapeutic DNA is not actually incorporated in to that of the host cell, multiple treatments are required to effect a change.

Why not use gene therapy?

Although the idea is clever and the system elegant, unfortunately, gene therapy has not been proven very successful in randomized clinical trials and is not approved by the Food and Drug Administration (FDA). All gene therapy treatments done today are considered purely experimental. The first successful gene therapy treatment was done September 14, 1990. A four-year-old girl born with a rare disorder called Combined Severe Immune Deficiency (SCID); she lacked a normal immune system. These patients often succumb to infections and rarely live to their adult years. Doctors were able to remove some of the girl's white blood cells and inserted the missing gene into them via a viral vector. They allowed the cells to grow and multiply in the lab and then infused all of the genetically altered cells back into her bloodstream. The young girl improved dramatically-- she no longer suffered from recurrent infections and was allowed to attend school for the first time. This was not a cure as white blood cells only last for a few months, but the procedure could be repeated and her life prolonged.

Unfortunately, nine years later gene therapy suffered a tremendous set back. A young (18 year old) boy who was participating in a gene therapy trial died from multiple organ failure suffered within four days of starting his treatment. His death was thought to have been triggered by a severe immune response to the virus vector used. One year ago this month, the FDA temporarily stopped all gene therapy trials using a certain family of viruses called retroviruses. This action was taken in response to the announcement that two other young children with SCID who were successfully treated in France with gene therapy developed leukemia.

How does gene therapy apply to cancer treatment?

Researchers have tried to use gene therapy in an attempt to boost the immune system and thus to improve the body's natural ability to fight cancer. Gene therapy has also been used to try to make the cancer cells more sensitive to chemotherapy. Other strategies include trying to induce tumor cell death by introducing DNA that would promote the killing of these cancer cells. Currently there are a few ongoing gene therapy trials for cancer.

In one study, viruses were injected into patients with prostate cancer. Once inside the human cell, the engineered DNA carried by the virus instructed the call to rapidly replicate multiple copies of the viral genome. Such a robust replication would cause the prostate cancer cell to burst, as it would be unable to contain the multiple viral copies. The result is death of the tumor cell and the unleashing of multiple viral copies ready to infect other adjacent cancer cells. This method was tested on twenty participants with prostate cancer following radiation therapy by Cell Genesys Inc. in California. A little fewer than half the patients had a 25% reduction in their prostate specific antigen (PSA) level. No serious side effects were reported in this trial.

A slightly different gene therapy method is one used in melanoma trials. A virus that contained a tumor suppressor gene was injected directly into a melanoma tumor in human patients. The most intense tumor cell kill was at the center of the injection with the cells furthest away from the site of the injection suffering little damage. There is some speculation that the virus also may have also caused an immune system activation that could have helped the killing of the tumor cells. More importantly, again, this trial did not report any significant side effects.

Activating the immune system is a commonly used application of gene therapy. There is evidence that injected tumor cells induce an immune reaction against the native tumor. This observation led Cell Genesys Inc to develop two potential prostate cancer vaccines. The company prepared two prostate cancer cell lines that secrete a certain protein. This protein was isolated and is now being investigated as a potential vaccine. If one were to introduce the protein to a man with prostate cancer, then perhaps his immune system would recognize it as foreign and mount an immune response. This procedure has the potential to delay disease progression. In a phase II clinical trial the vaccine was injected into 65 patients with metastatic prostate cancer. Since prostate cancer metastasizes to bone, researchers used the level of bone degradation by the metastasis as an indicator of cancer activity. Patients who received the vaccine were evaluated for bone degradation over a six-month period. Twenty-seven of these patients were noted to have a decrease in their bone degradation activity. This decrease was interpreted as an arrest or a deceleration in tumor progression.

Despite on going clinical trials, gene therapy is far from curing cancer but the potential remains enormous and the applications are vast.

What are the ethical questions surrounding gene therapy?

Multiple ethical questions arose with the development of this powerful technique. Critics have expressed concern that some may want to use gene therapy to change certain traits that may not necessarily be considered diseases. How do we define what is normal and what is a disorder? Furthermore, who makes such decisions? What one may consider a mild disability may be considered a disease by another. Other concerned critics are fearful that gene therapy could be misdirected at unborn babies to try to change or prevent certain traits from being passed on.

The cost of gene therapy must also be considered. Currently it is exorbitantly expensive and therefore not accessible by all. The question of who should pay for this procedure is still undecided.

As with any powerful tool there is the fear of misuse and abuse; but in the right hands it holds tremendous potential for all kinds of genetic disorders, infectious diseases, autoimmune problems and of course, cancer.