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Gene therapy helps treat diseases.
by Tim Ward
Several years ago, the Human Genome Project was begun to identify every human gene. The project should be completed in the next few years and has already given us an incredible amount of knowledge about our own genes. But what good is that knowledge without a useful application?
The next step is to figure out what we can do with that knowledge. One of the first goal is to cure genetic diseases, or diseases that stem from a defective or missing gene. The gene would need to be repaired or replaced in order to work properly.
In 1990, researchers began experimenting with Gene Therapy on humans. According to Jim Wilson, the director of The University of Pennsylvania’s Institute for Human Gene Therapy, “gene therapy is a novel approach to treating diseases based on modifying the expression of a person’s genes toward a therapeutic goal.” It alters or replaces the gene and therefore corrects the disease. There are two basic forms of gene therapy: one that is corrective for the patient and not passed on to the next generation (somatic), and one that will be inherited by subsequent generations (germline). Research in germline gene therapy has been minimal, “largely for technical and ethical reasons,” according to Wilson.
Somatic gene therapy repairs the defective gene by manipulating its expression in a manner that is beneficial to the patient. Now we can use the information that the Human Genome Project has given us — but how?
Many diseases, such as cystic fibrosis or hemophilia, are caused by an inherited defect in a single gene (monogenic). Monogenic inherited diseases are the most obvious place to start. By altering or replacing that gene, doctors can help that patient live a longer, healthier life. Sometimes the affected gene is non-active and needs to be replaced and other times it can be activated by altering or controlling the expression of the gene. But how do you go about altering a gene in a human being?
One way is to take specific cells from the patient and introduce the altered gene into the cells in a lab setting. This process is called the ex-vivo approach or the indirect method. The corrected cells are then implanted back into the patient. The direct method, or in-vivo approach, involves injecting the patient with the therapeutic genes and letting the alterations occur within the patient’s body. The in-vivo approach is now used in most cases, but several years ago, researchers were confronted with a problem. How can you direct the therapeutic genes toward the desired target cells?
This involves the use of vectors. Vectors are the mechanisms that deliver the therapeutic genes to the target cells. Many vectors are modified versions of viruses. Viruses have proven to be very effective at, “targeting certain cells and delivering genome, which unfortunately leads to disease”said Wilson. He goes on to say that,”our challenge is to remove the disease causing components of the virus and insert recombinant genes that will be therapeutic to the patient.” To be effective, the virus must be able to deliver the genetic material properly and effectively die. Injecting a patient with a virus can be a dangerous proposition if its disease causing aspects are not turned off. So how do researchers go about choosing the proper virus?
Adenoviruses are especially drawn to the respiratory system. Adenoviruses are responsible for diseases such as the common cold and were the first vector to be used in in-vivo gene therapy for the treatment of cystic fibrosis. These vectors are only effective in cells that are actively dividing. If the cells are not dividing, then the therapeutic gene never has an opportunity to get copied into the infected cell.
In this year’s January 29th issue of Science, Dr. Inder Verma of the Salk Institute for Biological Studies in La Jolla, California explained that, “If a cell is normally not dividing, like a brain cell, or a liver cell or a stem cell—which makes the blood cells—then you can’t use most ways of introducing genes.” Since a disease like hemophilia, which doesn’t allow a person’s blood to clot properly, originates in the stem cells, how can researchers develop a vector that will help these patients?
Retroviruses can alter the genes of a cell that is not dividing and are the most common form of viral vector being used today. Retroviruses are the cause of many cancers in humans and include the human immunodeficiency virus (HIV) that causes AIDS. Because of HIV’s voracious ability to modify another cells genetic material, Dr Verma is currently attempting to use it as a vector for gene therapy, and thus far his studies have been limited to mice. A retrovirus was used in the first therapeutic study of gene therapy involving patients suffering from an inherited disorder, adenosine deaminase deficiency (ADA), which weakens their immune system. Retroviruses are commonly used today as vectors for gene therapy, and the National Institute of Health (NIH) states that of the 125 approved forms of gene therapy, 63% of them use retroviruses.
Gene therapy is used mostly in cancer studies, but it can be used on a host of other genetic diseases. Parkinson’s disease affects nearly 1.5 million Americans according to the NIH. The disease can cause a person to be immobilized and at very least, to suffer from continuous tremors. AIDS is another disease scientists are attempting to cure with the use of gene therapy. The retrovirus that causes AIDS changes a cell’s genetic material. Scientists are looking into ways to change them back. Where does that lead us today?
As gene therapy celebrates its tenth birthday, researchers are looking back to see if it has lived up to its hype. The studies done so far have been cautious at best and focus mainly on the therapy’s safety. Over the last ten years, its effectiveness may be open to debate, but it has proven to be safe. However, an 18-year-old Tuscon, Arizona man recently died after having gene therapy at the University of Pennsylvania. In this case, the scientists were trying to combat a rare liver disease by using a high amount of an adenovirus to deliver the therapeutic genes directly into the liver. Four days later, Jesse Gelsinger was dead. In response to Gelsinger’s death, the Food and Drug Administration (FDA) decided to temporarily stop two other experiments of this form of gene therapy.
The FDA has only limited experiments that inject a high level of adenovirus into the liver, and the decision does not affect any other studies. As more studies are completed, we will begin to have a better feel for the future of gene therapy. Until then, we are left marveling at its possibilities.
