Gene Therapy for Mental Illness: Just Around the Corner?

Although gene therapy is in the earliest stages of development, it may still offer some benefits to psychiatry within the next five to 15 years, a scientist working in the field presages.

He is Robert Sapolsky, Ph.D., a professor of neurology and neurological sciences at Stanford University School of Medicine. He made the prediction at APA’s 2001 annual meeting in New Orleans in May, during a talk titled “Gene Therapy and Its Potential Application to Psychiatry.”

First, he reported, he and some other scientists have already managed to alter the brains and behaviors of research animals using gene therapy. For instance, one scientist used it to change rodents’ reactions to abusive substances such as cocaine.

Another researcher used gene therapy to turn polygamous rodents into monogamous ones. Still other investigators have succeeded in introducing genes into the hippocampus region of rodents’ brains and thereby altering the animals’ learning and memory. Sapolsky and his colleagues have successfully used gene therapy in rats not only to counter the neuronal damage inflicted by stroke, but also to save neuronal function.

And in some cases, researchers have even successfully introduced genes from one animal species into another, and they view this capability as perhaps paving the way for gene therapies. For example, Sapolsky pointed out, there are some turtle species that are “stupendously resistant” to the danger of not getting enough oxygen in their brains and bodies. “These guys can dive to some absurd depth and don’t get brain damage because they have brainstem neurons that are resistant to a deficiency in oxygen,” he said. “Researchers are looking for the relevant genes in those brainstem neurons and are then planning to plunk those genes down in the frontal cortex of somebody getting stroke damage,” in the hopes that the genes will counter the damage.

“All of this is very exciting,” Sapolsky stated. “Two years ago, I would have said, ‘No way in hell is this going to get here in the foreseeable future.’ But it is getting closer.”

Yet, he stressed, there are some big hurdles to overcome before such techniques can be routinely used in patients, and especially in patients with psychiatric disorders.

For example, say a gene has been identified that could lessen bipolar disorder, and doctors want to get it into the brain neurons of bipolar patients to improve their illness. But how are they going to do it?

“This is not a trivial challenge,” Sapolsky explained. “One of the central dogmas of the brain is. . .we have pretty much all the neurons we are ever going to have by age 4 or 5, . . .and that ends up being a huge limitation in gene therapy for the simple reason that almost all gene therapy techniques used outside the brain, the sorts of techniques that are so simple now, are built around the need of cells still dividing, replicating their DNA, because that is the point where you slip in the novel DNA. Thus, standard vectors like retroviruses will not work in adult brain neurons, because they operate by slipping into dividing cells, and adult brain neurons are not dividing.”

But might there be some viruses that could get into adult brain neurons even though the neurons are not dividing, and that thus might be used to ferry therapeutic genes into adult brain neurons? Yes, Sapolsky said. Adenoviruses are capable of this feat. “But there is a huge potential danger with them,” he stressed. It was an adenovirus gene carrier that killed a young patient who agreed to undergo gene therapy for a rare liver condition at the University of Pennsylvania in 1999. Researchers still need to come up with a virus or some technique that can slip a therapeutic gene into adult brain neurons, yet not cause a serious risk to patients, he said.

Still another problem that needs solving, Sapolsky pointed out, is to find some way to get therapeutic genes and their transporters into the human brain without injecting them through the skull. Currently, that is the only tactic available. If such material is injected into the bloodstream or cerebrospinal fluid, it cannot cross the brain’s blood-brain barrier to get inside the brain. The same holds true for material inhaled through the nose.

And if gene therapy is to benefit people with psychiatric disorders, it will have to be capable of exerting its effects over the long term, Sapolsky declared. Yet gene therapy is not capable of exerting such long-term effects at this point in its development. For instance, unless gene therapy is given to a rat within four hours of having a stroke, it does not work, Sapolsky and his colleagues have found.

Nonetheless, these and other obstacles to gene therapy for neurological and psychiatric conditions will eventually be overcome, Sapolsky believes. For example, molecular virologists are now designing hybrid viruses that may be able to slip through the brain’s blood-brain barrier and thus transport therapeutic genes from the bloodstream into the brain. And when such obstacles have been overcome, gene therapy will become available to treat at least some psychiatric disorders, Sapolsky suggested.

But when such therapy becomes available, exactly what will that mean to psychiatrists? Will it replace existing treatments? Not at all, Sapolsky reassured them. “You guys are still going to have to give your patients medications; you will still need to talk with them,” he said. “This is not going to put you out of business in terms of the traditional approaches.”

In short, gene therapies will complement traditional treatments, not replace them.

But what should perhaps be of more concern to psychiatrists, Sapolsky pointed out, is what may be coming in gene therapy a few more years down the road. And that is the use of gene therapy to alter brain neurons in human fetuses. True, such capabilities might lead to the correction of genes that help cause psychiatric disorders, which might be good in principle. Yet such a capability will also “be filled with incredible ethical pitfalls about what counts as broken and how you go about fixing it,” he said.

To wit: Should gene therapy be used to change people’s personalities before they are born? “I’m not clear about that one at all,” Sapolsky admitted. “What we have here, of course, is the incredibly slippery slope where we are no longer talking about people’s diseases, but about what makes them individuals.”

In any event, the possibility of using gene therapy to alter human fetuses “is not completely out of the question at this point,” he cautioned. “We are now in the pioneering days of doing surgery on fetuses, doing corrective preemptive moves. So it will eventually be possible to do gene therapy on human fetuses. . .not soon, but it will be there.” ▪