Major Finding: UPDRS motor scores improved a mean of 8.1 points in patients who received AAV2-GAD, which was significantly more than the 4.7-point improvement seen in patients who underwent a sham procedure.
Data Source: Phase II trial of 45 Parkinson's disease patients with UPDRS motor scores of 25 or greater.
Disclosures: Neurologix funded the trial. Many of the investigators reported serving as speakers or consultants to or receiving grant funding from many companies that manufacture treatments for Parkinson's disease. Dr. Hutchinson had no financial conflicts to disclose.
Direct infusion of the gene for glutamic acid decarboxylase into the subthalamic nucleus of patients with Parkinson's disease significantly improved measures of motor function, compared with patients who underwent a sham procedure, according to the results of a phase II trial in 45 patients.
The study was “the first successful randomized, double-blind gene therapy trial for a neurological disorder” and serves as a proof of concept for similar studies, justifying its continued development, Dr. Peter A. LeWitt of Wayne State University, Detroit, and his colleagues reported.
However, glutamic acid decarboxylase (GAD) gene therapy is not the only type of gene therapy under investigation for Parkinson's disease. A separate phase II trial with the gene for the neurotrophic factor neurturin is now enrolling patients.
In the study conducted by Dr. LeWitt and his associates, 22 Parkinson's patients with Unified Parkinson's Disease Rating Scale (UPDRS) motor scores of 25 or more were randomized to gene therapy and 23 were randomized to sham surgery. The gene therapy involved inserting the GAD gene into the subthalamic nucleus using the adeno-associated viral vector, AAV2.
GAD is the rate-limiting enzyme for the neurotransmitter gamma-aminobutyric acid (GABA). The destruction of nigrostriatal dopaminergic neurons in Parkinson's disease alters the dynamics of inhibitory GABA input to the subthalamic nucleus, which worsens parkinsonian symptoms. Improvement of symptoms has been shown previously with infusions of a GABA agonist into the subthalamic nucleus of Parkinson's disease patients during surgery for deep brain stimulation and also in animal models of parkinsonism.
After 6 months, patients in the AAV2-GAD group showed a 23% improvement (an average 8.1-point decrease) in UPDRS scores in the “off” state (while not on medications), compared with a 13% improvement (an average 4.7-point decrease) in the sham group (Lancet Neurol. 2011 March 17 [doi:10.1016/S1474-4422(11)70039-4]).
“The change of UPDRS scores from baseline differed significantly between treatment groups across all three postoperative time points” at 1, 3, and 6 months, the researchers noted.
The only severe adverse event reported during the study period was a case of bowel obstruction in the AAV2-GAD group. Mild and moderate adverse events included headaches and nausea.
In addition, the investigator's clinical global impression of Parkinson's disease severity improved significantly from baseline to 6 months in the treatment group vs. the sham group (3.4 vs. 3.9).
The patients' ages ranged from 30 to 75 years. A total of 6 patients in the treatment group and 2 in the sham group did not receive the complete intervention, leaving efficacy groups of 16 and 21, respectively.
The findings were limited by the study's small size and the possibility of inadequate blinding of the procedures because the patients were awake during their surgeries. However, “it is unlikely that the benefits in the AAV2-GAD treatment group were caused by the temporary placement of catheters in the subthalamic nucleus rather than from the infusion of the gene product,” the researchers wrote.
Although the study findings are promising, questions remain as to how long the effects of the gene therapy will last and what advantages it might have over deep brain stimulation, Dr. Michael Hutchinson of New York University, wrote in an accompanying editorial. The added value of the study is that the placebo effect is not large enough to explain the benefits of gene therapy seen in open-label surgical trials, he said (Lancet Neurol. 2011 March 17 [doi:10.1016/S1474-4422(11)70041-2]).
A separate investigational gene therapy treatment for Parkinson's disease, called CERE-120, proved to be safe but lacked efficacy in a recent randomized, sham-controlled, phase II trial that was sponsored by Ceregene Inc. (Lancet Neurol. 2010;9:1164-72). The investigators of that trial blamed its results on the failed delivery of the therapy (consisting of the AAV2 viral vector and the gene for neurturin, a member of the same protein family as glial-derived neurotrophic factor) to dopaminergic neurons.
In the trial, AAV2-neurturin was injected into an area of the brain called the putamen in patients with Parkinson's disease, where the nerve terminals of degenerating dopaminergic neurons reside. However, the investigators realized that neurturin was not being transported effectively to the cell bodies of the dopaminergic neurons, which reside in the substantia nigra (Mov. Disord. 2011;26:27-36).