ARTICLE IN BRIEF
- ✓ Investigators used a novel type PET that show how gene therapy corrected abnormal motor network functioning in patients with Parkinson disease on the treated side of the brain in an area responsible for movement while having no effect on networks on the other side of the brain or those associated with cognitive symptoms.
Last June, researchers reported that an experimental gene therapy procedure had “normalized” dysfunctional motor networks in a small group of patients with Parkinson disease, significantly reducing their clinical symptoms. Now they have snapshots showing how it works.
In a follow-up paper published in the Dec. 4, 2007 issue of the Proceedings of the National Academy of Sciences, the investigators published data gathered from the same patients using a novel type PET that they have been developing for several years. The images show how treatment corrected abnormal motor network functioning on the treated side of the brain in an area responsible for movement while having no effect on networks on the other side of the brain or those associated with cognitive symptoms.
Of clinical importance, the changes correlated with improved outcomes in the 12 patients with advanced disease. Scans also detected differences in responses between dose groups, with the highest gene therapy dose demonstrating the longer-lasting effect.
At the study's outset, patients all showed abnormal elevations in the activity of metabolic networks associated with both motor and cognitive functioning in PD patients. After treatment, the researchers observed significant reductions in thalamic metabolism on the side receiving therapeutic gene infusion, with concurrent metabolic increases in other motor and pre-motor cortical regions of the brain.
The imaging technique, called fluorodeoxyglucose (FDG), or FDG PET, measures changes in glucose metabolism in neural networks — essentially how much energy is being used and where. The procedure was developed by lead authors Andrew Feigin, MD, and David Eidelberg, MD, of The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System in Manhasset, NY, in collaboration with Michael Kaplitt, MD, of Weill Cornell Medical Center in Manhattan, and other researchers at Weill Cornell, Albert Einstein College of Medicine, Bronx, NY, and Ohio State University, Columbus.
“Brain networks are usually studied to examine the natural history of a neurodegenerative disease process, but we've applied it in an entirely different way to show how an experimental therapy can suppress network abnormalities,” Dr. Eidelberg told Neurology Today in a telephone interview. “FDG PET confirmed the action of this gene therapy in normalizing motor network activity.”
In PD, the brain's precise system of metabolic checks and balances grows increasingly more erratic in areas that control movement, such as the subthalamic nucleus (STN) and the globus pallidus (Gpi). This results in the disease's characteristic motor symptoms.
In the study, the images showed motor networks on the untreated side of a patient's body continued to become more dysfunctional while those on the treated side improved. Further, motor network improvements correlated with better disability ratings among the patients were evaluated with standardized clinical assessment tools, said Dr. Eidelberg, who directs the Center for Neurosciences at The Feinstein Institute for Medical Research.
“This is good news because you want to make sure treatment does not make things worse. This is why these brain scans were so critical. Having this information from a PET scan allows us to know that [the improvement] we're seeing is real.”
He noted that same scanning could also be used in the future to evaluate patients' responses to experimental therapies for other neurological diseases, as well as how individual patients are responding to current treatment for PD.
“The quantification of treatment-mediated changes in the activity of these metabolic networks may provide an objective means of gauging the effects of [other] experimental antiparkinsonian therapy.”
Work in Progress
Last July, the team reported in the journal Brain that their research with PET and gene therapy indicated that two discrete brain networks — one that regulates movement and another that affects cognition — are affected in PD.
It was the first longitudinal study of using brain imaging to track changes in these two networks over time, and helps explain why PD patients experience a range of different disabling symptoms, according to Dr. Eidelberg.
One month earlier, the team published the results of the phase 1 gene therapy trial in the June 2007 issue of The Lancet.
In that study, patients had had unilateral surgical infusion of a virus that expressed glutamic acid decarboxylase (AAV-GAD), a gene that makes an inhibitory chemical called GABA. GABA inhibits activity in a key part of the motor network in PD. Each subject were scanned prior to undergoing surgery, six months after the procedure, and again after one year.
The dose-escalating trial was the world's first study to use a viral vector for the treatment of an adult neurological disease.
“It took us nearly two decades of hard work to get there, but the success of the trial sets the foundation for the use of gene therapy against neurological diseases in general,” said Dr. Eidelberg. “We were able to show that genetic modification of the patient's own brain cells can be done safely - potentially opening up gene therapy for a host of brain disorders.”
Prior research has suggested that the motor symptoms of PD are associated with increased expression of an abnormal disease-related covariance pattern characterized by increases in metabolic activity in the globus pallidus and the subthalamic nucleus, with relative reductions in premotor and parietal association regions, according to the researchers.
Evidence has also shown that pathological expression is reduced by therapeutic lesioning or deep brain stimulation (DBS) of the motor portions of the Gpi and the STN, and that these network changes correlate with clinical outcomes after treatment. In contrast, these interventions do not affect the activity of a unique and distinct prefrontal-parietal metabolic network associated with memory and executive functioning in nondemented PD patients.
Taken together, the three studies indicate that unilateral STN AAV-GAD gene therapy may modulate abnormal network activity and gradually improve PD symptoms. The reported therapeutic benefits are similar to those achieved with other surgical interventions, including lesioning and DBS. STN is the preferred surgical approach for advanced Parkinson's disease — “the gold standard,” Dr. Eidelberg said, but not appropriate on all patients.
Phase 2 Study Pending
Because the phase1 study was an unblinded open-label trial, and all patients eventually received treatment, the possibility of a placebo effect influencing the therapy's efficacy was recognized early on as a limitation in the phase I trial, something the group hopes to address in another study, Dr. Eidelberg told Neurology Today.
“We're in the finals steps with the FDA,” he said. The phase 2 trial will be blinded and involve a larger number of patients, using bilateral procedures and sham surgery as a control, he explained.
“One of the benefits of PET is that it can provide predictive confirmation of observed changes in patients, which is very useful in evaluating therapy,” according to Dr. Eidelberg. He said he is optimistic that the results will be confirmed in the next phase because the PET scans are a fairly objective record of changes in the brain networks.
“In the phase 1 trial observers knew which subjects were the surgical patients, but the computer didn't,” he noted. “For [neurologists], the important finding is that the changes seen on the PET scans correlated with clinical outcomes. It's not happening in the abstract — these improvements are what we're seeing in patients.”
Neurology Professor A. Jon Stoessl, MD, director of the Pacific Parkinson's Research Center at the University of British Columbia, in Vancouver, said the findings should encourage patients, clinicians, and PD researchers.
“I think the study provides pretty strong evidence of the affect of this [gene therapy] treatment and offers very eloquent confirmation of clinical results,” he told Neurology Today in a telephone interview.
“PET is typically used to look at a disease process, but here it has been used to look at activity in the dopamine system by examining patterns of glucose use in the overall activation pattern. This group of researchers has a very strong track record and I think that their approach was very appropriate considering this type of gene therapy as an intervention.”
Dr. Stoessl, who serves as the Canada Research Chair in Parkinson Disease, noted however that it may not be appropriate in evaluating other types of gene therapy. “Essentially what they have done is provide complementary information for the initial trial,” he noted.