During gene therapy, physicians deliver genetic material to cells in the body by infusing a carrier molecule called a vector. This vector carries a healthy gene designed to replace a missing or altered gene. They may also be used to stimulate the body’s immune system, modify cells to make them more sensitive to other treatments, or alter the body’s ability to produce new blood vessels.
Viruses are the most commonly used vectors, however, perfecting their use presents one of the prime challenges to researchers. “We’re working to modify the vectors, so they accomplish effective gene therapy by making viruses targetable to specific cells,” says David T. Curiel, MD, PhD, director of the Division of Human Gene Therapy at the University of Alabama at Birmingham.
Gene Therapy’s History
Early work in gene therapy was aimed at correcting mutations that caused inherited genetic diseases. W. French Anderson, MD, and his former colleagues at the National Institutes of Health (NIH), completed the first successful human gene-therapy treatment, in 1990, on a four-year-old child with a rare genetic disease. Since then, in trials, physicians have used gene therapy to attempt to treat
, and other genetic diseases. However, correcting defects that cause inherited diseases has proven more difficult than expected. One of the reasons is treatment must continue throughout the patient’s life without creating new problems.
Researchers soon discovered gene therapy’s potential as a cancer treatment. Now a majority of the gene-therapy trials focus on using the technique in battling malignancies. “All you have to do is kill the cancer cells,” says Dr. Anderson, currently the director of the Gene Therapy Laboratories and a professor at the University of Southern California Keck School of Medicine. “If you are treating a genetic disease, vascular disease, arthritis or something else, you have to get the cell to function normally and not cause toxicity.”
Toxicity is less of an issue with cancer therapy, since most current treatments include side effects. “When you’re balancing a successful treatment with death, a little inflammation doesn’t matter that much,” Dr. Anderson says.
Potential for Treating Many Diseases
Clinical trials are ongoing for a multitude of conditions, such as autoimmune diseases, liver diseases, and acquired immunodeficiency syndrome. Wound healing may also lend itself to gene therapy.
Researchers at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, reported results of a gene therapy trial in the June 7, 2001
New England Journal of Medicine
. The investigators tested the safety of a nonviral gene therapy system to treat patients with severe hemophilia A. The researchers grew cells obtained from each patient’s skin cells and added a component involved in sequencing the gene that encodes factor VIII, the clotting factor hemophilia A patients lack. The patients noticed less bleeding and experienced no serious adverse events or long-term complications.
In September 2002, the
Journal of Cardiology
reported the results of a Phase I trial that looked at treating claudication (poor circulation) with vascular endothelial growth factor. About one-third of the patients developed edema (swelling) in their tissue and limbs. Another patient developed cancer, possibly as a result of the treatment. The investigators recommended further studies before using the treatment more widely.
A rare immune disorder called
chronic granulomatous disease
has been a major target for gene therapy because it is due to a single absent enzyme (protein). In 2006, German scientists reported successful treatment of adults with this disorder, apparently avoiding the risk of cancer that had plagued earlier attempts (see below).
Gene Therapy Risks
As with any treatment, gene therapy comes with risks. One young man died after experiencing a massive reaction to the vector after a gene-therapy infusion. “His death raised a red flag that gene therapy is not harmless,” Dr. Anderson says. “The risk of a major immune, inflammatory response remains.”
In France, two children developed leukemia-like syndromes after gene therapy because, unbeknownst to the physicians that treated them, the gene they received had cancer-causing properties. Physicians have learned from these events and have altered gene-therapy protocols accordingly. For example, now vectors are stripped of any content likely to cause an inflammatory reaction, and the gene given to the two girls in France is no longer being used. More than 3,000 people have now received gene therapy without experiencing serious side effects.
At first, many people voiced ethical concerns about gene therapy, but somatic gene therapy, a type of treatment that benefits living patients without altering their gene pool is now widely accepted. Public concern remains, however, about introducing genes into egg or sperm cells or altering a child’s genetic makeup before its birth. No one knows the long-term dangers. Errors in this type of application could have profound genetic effects on both the children and their descendants. Currently, this type of gene therapy is not allowed in the United States.
No one can say for sure when gene therapy will receive approval for use outside of clinical trials. Dr. Rosenberg considers it highly experimental. Drs. Anderson and Curiel share a more optimistic outlook and estimate a commercial gene-therapy treatment most likely a cancer treatment, may become available within five years. “We’re within a year of saying there has been a gene-therapy cure and a gene-therapy agent on the shelf,” Curiel says. “The field is doing pretty well for only [being] 15 years old.”
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Rajagopalan S, Trachtenberg J, Mohler J, Olin J, McBride S, et al. Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication.
Am J Cardiol
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