A molecule that has long been a source of hope as a potential Parkinson’s disease therapy will get a new chance to show its benefit. A team led by Krystof Bankiewicz at the University of California, San Francisco, plans a clinical trial of an experimental gene therapy using glial-derived neurotrophic factor (GDNF), a protein that helps keep neurons alive. The team is in the final stages of gaining approval from the U.S. Food and Drug Administration, and hopes its trial can address issues that marred previous trials.

Current Parkinson’s treatments control symptoms, but they don’t slow the disease’s progression. GDNF first showed promise as a treatment for Parkinson’s patients when scientists discovered that it could boost the survival of dopamine-producing neurons—cells that degenerate in the disease—back in 1993. But so far, the results in humans have not borne out those hopes. Early trials involving injecting the protein directly into the brain showed some promise, but a second, more comprehensive trial subsequently showed no benefit. Another recent trial that used a gene therapy approach to deliver a similar compound, neurturin, showed some signs of benefit but failed in its primary goal of improving symptoms after one year.

Bankiewicz believes that other attempts failed because they didn’t target the right tissue precisely enough. The first attempts, he said, injected the GDNF protein into the spaces near the brain regions of interest, where it failed to diffuse far enough into the brain. Infusing the treatment directly into the relevant brain tissue, he says, caused leakage into the surrounding fluid. “They all turned out to be negative, because the delivery was never controlled,” Bankiewicz says.

The new trial will introduce the gene encoding GDNF into the putamen, a brain area involved in Parkinson’s disease. The gene will be carried by a virus, and will be injected directly into the brain using a technique called convection-enhanced delivery, which uses positive pressure to drive fluid deep into targeted regions. The injection will include an MRI contrast agent, and the researchers will use an MRI-based imaging system to track the distribution of the treatment during delivery. Bankiewicz says the imaging system will allow the team to make sure the gene gets to where it’s needed.

Once incorporated into cells, the gene would drive the expression of GDNF protein; Bankiewicz says it should then travel to other areas of the brain affected by disease, transported along axons, the long tails of neurons that connect brain regions.

It remains to be seen whether a more precise delivery system is the answer, and scientists disagree over which factors need improvement: the vector that contains the genes, the delivery system, the targeting of relevant brain regions, the types of patients that are studied—or even the gene itself. Andrew Feigin, a neuroscientist at North Shore University Hospital, says that the recent setback in the neurturin trial casts doubt on whether a similar approach will work with GDNF. “It still remains to be seen whether GDNF really is something that helps people with Parkinson’s disease,” he says.

Ronald Mandel, a neuroscientist at University of Florida, is also working on a GDNF gene therapy. He’s optimistic that GDNF could help Parkinson’s patients, but he believes it should be tested in patients at the early stages of the disease—before the dopamine-producing cells have become severely diseased and die off. Getting approval to test therapies in such patients, however, is very difficult.