By Lisa Seachrist
Discovering a new gene and its function quickly leads to speculation of potential gene therapies that can deliver a corrective gene product directly to defective cells.
However, the promise and excitement of those discoveries yields to the harsh reality that gene therapy has barely entered its infancy. The problem only becomes more difficult when the brain is the target for gene therapy.
Even so, Martha Bohn, of the University of Rochester, and Beverly Davidson, of the University of Iowa College of Medicine, successfully inserted a gene into rat brains that protected the animal from Parkinson's disease.
"What we have shown, is that the theory works," Bohn said. "We can insert a gene into a rat's brain, and have an affect."
Parkinson's disease is characterized by a progressive loss of dopaminergic neurons * nerve cells that produce the neural transmitter dopamine * in a specific part of the brain called the substantia nigra. Current therapies aim at increasing the levels of dopamine in the brain, but do nothing to halt the destruction of these cells.
Several studies in rat and non-human primate models of Parkinson's have shown that a neural growth factor, glial cell-derived neurotrophic factor (GDNF), could protect dopaminergic neurons. However, such a treatment would require continuous infusion of the cerebrospinal fluid with quantities of GDNF that are harmful to other brain cells.
"Gene therapy offers the opportunity to produce GDNF in the precise area of the brain that would benefit," Bohn said. "But, that has been difficult to achieve."
Bohn and her colleagues, however, engineered an adenovirus to produce GDNF when it infects brain cells. The researchers injected this engineered virus into rat brains. They chose to infect cells that were directly above the dopaminergic cells.
"We have a very precise method of injecting the adenovirus," Bohn said. "It allows us to get gene expression in the vicinity of the susceptible cells."
The researchers then injected the rats with a neurotoxin, 6-OHDA, which specifically destroys dopaminergic cells. As the researcher report in the Feb. 7, 1997, Science, the gene therapy protected these cells.
"The adenovirus infected cells produced nanogram levels of GDNF," Bohn said. "And, it almost completely protected the dopaminergic neurons. Only 10 percent to 20 percent of the nerve cells died."
Bohn also noted that after two months, the infected cells in the rat brain were still producing nanogram levels of GDNF. However, it remains to be seen how long the effect will last.
When injected into the brain, adenovirus, unfortunately, can trigger an immune reaction that ultimately damages the brain. Bohn and her colleagues avoided this pitfall by using a strain of rat that mounts a much less extreme immune response and by injecting only very small amounts of virus. "While this works for the rat, preventing brain damage is the major problem with using these vectors in humans," Bohn said. "As a result, [adenovirus] may not be the ideal vector for the human brain."
Nevertheless, simply transferring the gene into the cells and showing it protects against Parkinson's proves that it is possible to deliver genes to specific areas in the brain. "This is a very exciting finding," said Eugene Redmond, director of the Yale University Neural Transplant Program. "It's a proof of principle. It's the first time anyone has shown a function effect for a vector delivered to the brain."
Redmond warned, however, that it could be a decade before scientists engineer a vector that is safe enough for use in humans. Even though Bohn's experiment showed that GDNF could protect dopaminergic cells from Parkinson's-like damage, Redmond pointed out that nearly 90 percent of all these brain cells have died by the time a patient shows symptoms.
"It's hard to believe that growth factors can bring back the dead," Redmond said.
Those vector-delivered growth factors may provide avenues to enhance other Parkinson's strategies. Redmond, who works on neural transplantation of fetal cells into the brains of Parkinson's patients, noted that growth factors like GDNF may support the growth of these transplanted cells.
"Right now, only 5 percent or so of the transplanted cells survive," he said. "If we could boost the survival to 50 percent, that could make a huge difference for these patients."
However, Bohn noted that GDNF may protect the dopaminergic cells that a person has left which could provide an enormous benefit to patients.
She and her colleagues have begun studies to assess the rats' motor abilities to test the effects of the gene therapy protection. And, the team will work toward testing the procedure in nonhuman primates.
"Long-term, we need to get this into an animal that is closer to humans and develop vectors or synthetic delivery methods that won't cause immune reactions," Bohn said. "But, whatever the method, if we can get the gene into the right place, we may be able to produce an effect without adversely affecting other cells in the brain." *