BioEd Online

A potential gene therapy for Parkinson's disease can correct motor deficits in monkeys without causing the jerky, involuntary movements that often accompany long-term treatments for the disease. The approach is undergoing preliminary testing in a handful of human patients, who have all shown promising signs of improvement.

At present, the most common remedy for Parkinson's disease involves replacing dopamine — the neurotransmitter that is depleted in patients with the disease — by administering the dopamine precursor levodopa, or L-DOPA. Most patients initially regain near-normal motor control, but after several years on L-DOPA the majority become saddled with debilitating physical and psychological side effects.

To remedy the situation, Stéphane Palfi, a neurosurgeon at the French Atomic Energy Commission's Institute of Biomedical Imaging in Orsay, and his colleagues turned to gene therapy. First, they gave macaque monkeys a harsh neurotoxin that caused the animals to develop bodily tremors, unstable posture and severe joint rigidity — hallmarks of advanced Parkinson's disease. The researchers then injected the monkeys' brains with three genes essential for synthesizing dopamine.

They saw significant improvements in motor behaviour after just two weeks, without any visible adverse effects. "We don't see any problems in these monkeys," says Palfi. One animal even exhibited sustained recovery more than 3.5 years later. Notably, the monkeys did not display the jerky, uncontrolled movements that occur in most patients and monkeys after prolonged oral L-DOPA treatment.

This success in monkeys paves the way for future studies in humans, says Palfi, who reported his animal results today in the journal Science Translational Medicine¹. "This is the exact situation that we will face in the clinic," he says. Palfi's team has already tested two different doses of the three-gene-containing virus in six human patients, and is now investigating an intermediate dose that matches that used in the monkeys, with corrections for brain size. Once the researchers find the optimal dose, they plan to move the experimental treatment into Phase II trials, Palfi says.

All or nothing

Palfi's technique is not the only gene therapy currently being pursued for Parkinson's disease. Some researchers are delivering genes that provide growth factors to halt the death of dopamine-producing neurons. Others are introducing genes that inhibit the excessive neural activity associated with Parkinson's disease in the same way as the surgical process known as deep-brain stimulation. And yet others are focusing on single genes — rather than all three — with a role in dopamine synthesis.

But Palfi's team is the first to deliver all three of the dopamine genes in a single viral vector in primates. This approach aims to eliminate the need for L-DOPA and its associated side effects. But the technique would mean that clinicians would no longer be able to fine-tune the levels of dopamine in the brain to meet the needs of the patient, notes Jamie Eberling, associate director of research programmes at the Michael J. Fox Foundation for Parkinson's Research in New York City.

As a faculty member at the Lawrence Berkeley National Laboratory in Berkeley, California, Eberling was involved in a Phase I trial for a gene therapy that replaced only one of the dopamine-associated genes in order to reduce the dosage of L-DOPA and minimize the side effects². With the single-gene approach, "we could control dopamine levels despite the fact that we could not control gene expression; with this three-gene approach they can't control either," says Eberling. "So far what they've seen seems very safe, but it is a potential issue."

Michael Kaplitt, a neurosurgeon at the Weill Cornell Medical College in New York, who helped to run a gene-therapy trial to mitigate hyperactive neural responses³, cautions that the monkey results are difficult to extrapolate to humans because the chemical used to induce parkinsonian symptoms destroys neurons much more rapidly than does the disease in humans. Even so, he says, "the more that we have animal data that supports a human study, and the more human data we have, the more we'll be able to understand what has been the barrier to ultimate successful development and translation [of gene therapies] to the clinic."