Gene therapy shows real promise in Parkinson’s


A multicentre gene therapy trial for patients with advanced Parkinson’s disease demonstrated reduced symptoms of the progressive movement disorder, according to a new study published in Lancet Neurology.

A double-blind, sham-surgery controlled, randomised trial published online on 17 March has shown that bilateral delivery of AAV2-GAD in the subthalamic nucleus resulted in significant improvement in motor function for Parkinson’s patients. The authors have concluded that the efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson’s disease and shows the promise for gene therapy for neurological disorders.


Andrew Feigin, associate professor of neurology and molecular medicine, The Feinstein Institute for Medical Research in Manhasset, New York, USA, and others set out to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson’s disease.


The study was designed to deliver the gene for glutamic acid decarboxylase (GAD) packaged in inert viral vectors into the subthalamic nucleus. Glumatic acid decarboxylase makes an inhibitory chemical called GABA.  In Parkinson’s disease, the subthalamic nucleus is abnormally activated and this activity leads to the debilitating movement problems. The premise of the gene therapy is that the billions of AAV2- GAD viral vectors delivered into the subthalamic nucleus will increase GABA, thereby quieting this brain region.


Gene transfer of glutamic acid decarboxylase and other methods that modulate production of GABA in the subthalamic nucleus have previously been shown to improve basal ganglia function parkinsonism in animal models.




Over the period between November 2008 and May 2010, investigators enrolled 56 patients aged 30–75 years who had progressive levodopa-responsive Parkinson’s disease and an overnight off-medication unified Parkinson’s disease rating scale (UPDRS) motor score of 25 or more. Enrolment took place at seven centres in the USA.


All patients enrolled had a positron emission tomography brain scan before the surgery to confirm the diagnosis of Parkinson’s disease. Feigin and his colleagues found that 11 of 56 patients did not actually have Parkinson’s and they were excluded from the study.


Of 45 patients assessed for eligibility, 23 were randomised into the sham surgery arm of the study—they had a surgical procedure that did not penetrate the brain, and received infusions of saline under the skin rather than the active GAD-containing viral vectors—and 22 to AAV2-GAD infusions. Investigators assessed patients at one, three and six months after the genes were infused.



Feigin et al only included patients who received bilateral infusions delivered to the the subthalamic nucleus. There were a few cases where the pumps delivering the treatment (both AAV2-GAD and the placebo) malfunctioned during surgery and those cases were taken out of the analysis. The final analysis included 16 patients who received AAV2-GAD treatment and 21 who received the sham surgery.


The main outcome measure was a change on a rating scale that assesses motor symptoms. The treated group showed a 23% improvement on the United Parkinson’s Disease Rating Scale, compared to a 12% improvement in those who received sham surgery. Normally over a six-month period patient scores remain stable or worsen. The 12% improvement among the sham-treated group suggests a placebo response, said the authors.

At the six-month endpoint, United Parkinson’s Disease Rating Scale score for the AAV2-GAD group decreased by 8.1 points (SD 1.7, 23.1%; p<0.0001) and by 4.7 points in the sham group (1.5, 12.7%; p=0.003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the six-month course of the study.

One serious adverse event occurred within six months of surgery, a case of bowel obstruction occurred in the AAV2-GAD group. This was not attributed to treatment or the surgical procedure, and fully resolved.

Other adverse events were mild or moderate, likely related to surgery and resolved. The most common of these were headache (seven patients in the AAV2-GAD group vs. two in the sham group) and nausea (six vs. two).

“This is a completely novel treatment for advanced Parkinson’s disease,” said Feigin. “The treatment was remarkably well tolerated, with mostly only mild adverse events in the AAV2-GAD treated group that were felt to be unrelated to the treatment, and completely resolved,” he said. He added that other secondary clinical assessments also provided evidence for improvements from the gene therapy.

The trial was funded by Neurologix.