Gene Therapy for Parkinson’s Shows Promise

by Jim Schnabel

January 11, 2010

European researchers have reported a successful test of a gene therapy for Parkinson’s disease in monkeys. Designed to boost levels of the neurotransmitter dopamine in a brain region that controls voluntary movements, the therapy enabled the monkeys to recover most of their lost movement abilities within a few weeks. The animals maintained these improvements without significant side effects over the next year.

“It’s correcting the symptoms, not curing the disease itself,” says Bechir Jarraya, a neurosurgeon at Henri Mondor Hospital in Paris and first author on the study, which appeared in the Oct. 14 issue of Science Translational Medicine. Jarraya and his colleagues already are running initial, small-scale trials of the same gene therapy in people, hoping it will prove to be a better option for patients than current Parkinson’s treatments. “So far all the patients have improved.”

Three genes for dopamine

The gene therapy technique involves injecting a gene-carrying virus into the dorsal putamen, part of the brain’s striatum. In Parkinson’s disease, a midbrain region that normally supplies the dorsal putamen with dopamine stops doing so; neurons in the putamen therefore start to die, and as they do, the putamen loses its control over regions that regulate voluntary muscle movements. The three genes implanted in surviving putamen neurons by the therapy enable them to synthesize and resupply the dopamine normally lost in the disease.

Jarraya and his colleagues began their study by inducing a standard model of parkinsonism in 18 macacque monkeys. The researchers used a toxin to selectively destroy neurons in the substantia nigra, the midbrain region that normally supplies dopamine to the striatum. Within two weeks, the monkeys showed typical parkinsonian signs, including slow movements and tremors.

The researchers then injected the therapeutic genes into the dorsal putamens of six of the monkeys, splitting the remaining twelve animals into two control groups—one receiving no treatment, the other receiving an injected virus carrying a dummy gene instead of the three treatment genes.

Within two weeks of their injections, the treated monkeys showed significant improvement compared with the monkeys in both control groups. Within six weeks, their movements had become almost normal, while the untreated monkeys remained severely debilitated. The improvements in the treatment group lasted for the planned 12 months of the observation period. One of the monkeys was observed for 44 months, and maintained its improvements throughout.

The researchers developed the new therapy to overcome the shortcomings of the current standard therapy for Parkinson’s, the oral drug levodopa. A chemical precursor of dopamine that is processed into dopamine by enzymes in the brain, levodopa is delivered to the entire brain, not just to dopamine-depleted areas. Prolonged levodopa therapy also typically leads to “levodopa-induced dyskinesia,” in which a person experiences uncontrollable jerky movements for a while after taking each dose, and then may become immobile when his or her levodopa levels fall again.

This induced dyskinesia effect isn’t completely understood, but it does involve a long-term, possibly addiction-like alteration of striatal neurons by the drug. In the current study, the monkeys who received the gene therapy shortly after their symptoms began, and never received levodopa, did not develop the dyskinesias typically seen with long-term levodopa treatment. Non-gene-treated monkeys that received levodopa did develop dyskinesias.

The levodopa problem

The levodopa-treated monkeys later received the gene therapy and showed improvements, but their improvements were slower and ultimately less dramatic than those seen in the non-levodopa-treated monkeys—suggesting that the gene therapy might primarily help newly diagnosed, “levodopa-naïve” Parkinson’s patients.

Treating such patients with the gene therapy “is what we would love to do in the mid-to-long term,” Jarraya says. The initial set of clinical trials, though, will enroll more typical Parkinson’s patients, who have been taking levodopa for years, suffer from associated dyskinesias and thus have a greater need for a new therapy. The primary aim will be to see if and by how much their levodopa doses, and their dyskinesias, can be reduced.

These first trials in humans are likely to show less-dramatic results than those seen in the levodopa-naïve monkeys. Indeed, Jarraya says that in the initial human safety trials, patients have improved “in a variable way, so that some patients improved more than others, and in some of them we could reduce the [levodopa] treatment. But it’s too early to say more because [the trial] is not finished.”

The gene therapy developed by Jarraya’s group is not the only one being tested in people with Parkinson’s. Among the others is one that targets the brain’s subthalamic nucleus, which is abnormally hyperactive in the disease; by quieting it, the therapy tries to replicate the effects of deep brain stimulation. An earlier gene therapy, sponsored by a San Diego-based biotechnology company, was meant to protect striatal neurons from deteriorating by implanting genes for the production of a brain-cell growth factor; this approach showed relatively weak results in initial clinical trials and may not reach large-scale trials.

Gene-therapy approaches all have inherent risks, says Eugene Johnson, a professor of neurology at Washington University of St. Louis and chief scientific advisor to the Michael J. Fox Foundation for Parkinson’s Research. One is that by implanting new genes permanently into brain cells, without some sort of “off switch,” doctors would have no good options for modifying their effects in case the actions of the new genes turned harmful. The therapies also do not address the root causes of Parkinson’s, which are poorly understood and which lead to many non-motor symptoms, from dementia to sleep and digestive problems.

But Johnson, who helped to develop the growth-factor gene therapy, says that the test of the dopamine-replacement gene therapy in monkeys by Jarraya and colleagues is “certainly encouraging.” He notes, moreover, that the early trials of other gene therapies in Parkinson’s patients so far have shown no major adverse effects.

“At this point, you just have to wait and see whether the efficacy you demonstrated in these [animal] models of parkinsonism translates into a clinical benefit in real Parkinson’s patients,” Johnson says. “There’s an awful lot of human misery out there that these things potentially could have a big impact on.”