Judging by the stream of studies in the last few months, it seems the field of gene therapy is beginning to replace its troubled history with the beginnings of a promising future.
In September, researchers reported that viral delivery of a pigment gene allowed colorblind squirrel monkeys to see red and green for the first time, providing hopes that the technique could be used to treat colorblindness in humans. In October, transplant scientists showed they could bolster the health of donor lungs by supplying a gene coding for an anti-inflammatory molecule. Earlier this month came a report in which gene therapy was used to halt the progression of adrenoleukodystrophy, a fatal brain disease, in two young boys using a virus derived from HIV to deliver the gene for the missing enzyme. Finally, a study published today (November 11) in Science Translational Medicine reports that administering a gene blocking muscle breakdown to monkeys boosts the size and strength of their muscles -- suggesting such a treatment may one day help patients with degenerative muscle disorders.
With the flurry of recent successes, Mark Kay, director of the Human Gene Therapy program at Stanford University School of Medicine and one of the founders of the American Society of Gene and Cell Therapy, believes that "the mood in the field is pretty positive." Kay took time to chat with The Scientist about the progress that's been made in the field the hurdles still left to overcome.
The Scientist: Can you start by describing the outlook for gene therapy after these recent successes?
Mark Kay: These studies have provided a great model for the potential success of gene therapeutics. There is a lot of optimism in the gene therapy field right now that these therapies will work well. In the course of gene therapy research, there have been a lot of unanticipated hurdles, but in a relatively short time [since trials began in the 1980s], I think we have made a lot of progress.
TS: What kinds of conditions are best suited for gene therapy?
MK: There are a lot of conditions for which gene therapy could work. The easiest target appears to be single gene disorders, including adrenoleukodystrophy and blindness, where only a small percentage of cells need to be fixed.
Other disorders caused by a single gene are more complicated to treat, however. For instance, Duchene muscular dystrophy, which affects all the skeletal and cardiac muscle, requires correcting one gene, but the defect needs to be changed in a large number of cells to make a clinical treatment successful. Cancers, which deal with many different cells in the body, will also be difficult to cure with gene therapy, but perhaps when used in combination with other treatments, gene therapy may turn out to have therapeutic results.
TS: What do you see as the main technical hurdles that gene therapeutics has yet to overcome?
MK: I would lay out four main hurdles that we have to overcome:
1) First, it's essential to get a vector to the specific cells in high enough levels to produce the desired response but not have toxicity problems.
2) Once the vector with the encoded gene reaches the desired cell, it must be internalized and get to the nucleus. The cell has naturally implemented a lot of barriers to prevent this new DNA from interacting with the existing DNA, but viruses are good delivery tools because they have developed mechanisms to get passed these hurdles. Overcoming this difficulty has turned out to be more difficult than previously anticipated.
3) Once in nucleus, the new gene must be able to persist for the desired amount of time. The cell can sometimes shut the new gene off, making it ineffective.
4) The final main problem is the potential for an immune response. If the gene product is recognized as a foreign agent, the body can mount an attack against the vector or the protein.
Another general issue is determining how long the gene therapy should persist. If you're treating an infection or cancer, you only need gene therapy to last until the infection or cancer has been eliminated. But in genetic disorders, you need lifelong gene correction.
TS: Are there still safety concerns?
MK: People are always going to be cautious moving forward. We don't know for sure what the risks of some of these treatments might be. For instance, there is increasing evidence that the patients who developed leukemia [two children whose X-linked Severe Combined Immunodeficiency Disease was cured with gene therapy in the highly publicized 1998 trial later developed leukemia] may have a very disease-specific type of problem. Any time you're inserting new DNA into cells there will always be some risk that it will increase the chances of developing a malignancy. There are many medical treatments unrelated to gene therapy where the risk of developing cancer is reasonably high. For example, by treating one type of cancer, you may be using molecules that increase your risk of developing another type of cancer. As we continue to move into unknown territory in gene therapy, it will be important to watch for toxicity and longer-term side effects.
TS: What ethical issues remain that the field will still have to address?
MK: The bigger ethical dilemmas will likely come in the future when we have to decide where to draw the line in terms of what conditions we're willing to treat. Clearly gene therapy should be used to combat severe mental disorders or genetic diseases, but deciding whether to treat neurobehavioral disorders, such as depression or addiction, provides more of a gray area. And should we use gene therapy to enhance or select for certain traits, like higher IQ or athletic ability. Even though it's not possible to treat any of these disorders now, with more advances in gene therapy, people may start asking these questions in the future.
TS: What's the next frontier in the gene therapy?
MK: While most of gene therapy is focused on adding another copy of a functional gene, another path may be to design molecules that can turn off defective genes. For instance, in Huntington's disease, gene therapy could be used to turn off the defective gene that produces an abnormal protein.
I think one of the most important aspects for a lot of these diseases is to treat them early on, before the pathology has caused irreversible damage. Prevention is much more effective because it's much harder to fix a problem in a neurodegenerative disease or muscular dystrophy when the damage has already been done.
Editor's note (November 12): This post originally referred to the American Society of Gene Therapy. That organization changed its name to the American Society of Gene and Cell Therapy in May, 2009.The post has been updated with the current name.
Source: The scientist.com Magazine