March 19, 1999

Neuroscientist Robert Sapolsky, Ph.D., gave psychiatrists a look into the future of gene therapy for the brain during a presentation in San Francisco last month at the American College of Psychiatrists' annual meeting.

The good news is that within the next decade it may be possible to use gene therapy to halt the destructive aftermath of stroke or similar neurological insults, according to Sapolsky, a professor of biological sciences and neuroscience at Stanford University in Palo Alto, Calif. It will be longer, perhaps much longer, before neuro-degenerative diseases such as Alzheimer's and Parkinson's yield to the marvels of gene therapy, and even longer before the technology can be applied to psychiatric disorders.

Given the multiple causation of psychiatric disorders and the lack of clarity regarding the interaction between neuromolecular events, environment, and human behavior, it may be decades before gene therapy becomes more than a theoretical curiosity for psychiatry, Sapolsky observed.

"It's a bit of science fiction, but it's also reality," remarked moderator Eliot Sorel, M.D., a clinical professor of psychiatry and behavioral sciences at the George Washington University School of Medicine and Health Sciences in Washington, D.C.

The obstacles for psychiatric applications are formidable, and gene therapy is only in "the baby stage," Sapolsky commented. "We are only remotely beginning to even think about psychiatric disorders," he added.

Although now entirely theoretical, one vision of gene therapy for psychiatry relies on the notion that stress is a precipitating factor in many psychiatric disorders, explained Sapolsky.

"On a molecular level, what that would most helpfully suggest is a way to design vectors that are stress-sensitive-turned on by the same sort of signals that are involved in causing trouble in the first place," he told Psychiatric News. "The glucocorticoid scenario is one we are working on and making some progress with in the realm of neurological insults, but the principle can certainly be applied to psychiatric disorders-once one really emphatically emphasizes that this [model] is very, very simplistic." Glucocorticoids such as hydrocortisone and dexamethasone are associated with stress.

It may one day be possible to alter permanently someone's genetic endowment to eliminate obvious risk factors for psychiatric illness. Doing so, however, would imply changing the human genome, and where such changes involve personality rather than physical deformity, the ethical debate is sure to become heated, Sapolsky observed.

In the less distant future, however, gene therapy may provide clinicians with techniques for minimizing the neurotoxic cascade that follows stroke and similar neurological insults. Sapolsky and colleagues have already successfully used gene therapy on rats experimentally given a stroke. But moving from the bench to the bedside, even in stroke treatment, will require devising a gene therapy that does not rely on a carefully controlled laboratory environment to work, Sapolsky noted. "It's not in your neighborhood grocery yet," Sapolsky quipped, "but it's coming."

The key to gene therapy is figuring out how to get a desirable gene into target cells, using a virus or sometimes a modified bacterium as a "vector" for the desirable genes. One explanation likens the vector to a tiny Trojan Horse in which the inserted genes play the role of covert soldiers, although in this case they are intended to unleash their might for cellular protection rather than destruction.

The inserted genes are able to trigger the host cell to react in a specific way, as, for example, by enhancing the uptake of glucose following a stroke.

Scientists have favored the use of neurotropic viruses, such as herpes simplex virus and the adenoviruses, as vectors for inserting genes into target cells. These viruses have evolved to be able to get into cellular DNA and disrupt cellular mechanisms. Researchers strip out the pathogenic genes from these normally disease-causing viruses and replace those genes with genes designed to trigger a desired outcome in the target cell.

The first questions to ask in gene therapy research are "Can you find a vector system that is safe?" and "Does it do what you want it to do?," said Sapolsky. The problem is that vectors that work well, that is, that cause strong expression of a gene, may be dangerous, and those that are safe may be relatively weak in triggering gene expression. This is because strong vectors that more easily penetrate cellular DNA are more likely to trigger inflammation or otherwise damage the host cell, while weak vectors are less effective at penetrating cellular DNA.

The goal is to determine which genes should be "overexpressed" to counter a destructive process in the brain, said Sapolsky. In treating stroke, as opposed to neurodegenerative and psychiatric disorders, the effects of the inserted genes need last only a few hours and may be relatively localized to the immediate area of the insult, Sapolsky noted. But to even begin thinking about treating a psychiatric disorder, it will be necessary to design vectors that spread further, last longer, and are still minimally cytopathic, none of which has yet been achieved in animals, much less humans.

The Stanford team is "just gearing up" for its first research on human brain tissue (in a petri dish) to begin extending to humans the findings from animal research on countering the aftermath of stroke and other neurological insults, Sapolsky said.

-R.B.K.