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SAN DIEGO—Two novel gene therapies are well-tolerated in patients with Parkinson disease (PD), according to two teams of investigators who presented results from pilot trials here in April at the AAN Annual Meeting.

“Gene therapy approaches generally are designed to address the needs of patients with advanced disease who have already had deep brain stimulation,” said Chad Christine, MD, in an interview. Dr. Christine, who led one of the studies, is Assistant Professor of Neurology at the University of California-San Francisco (UCSF), where he specializes in Parkinson disease.

Mainly, deep brain stimulation has reduced fluctuations in response to medication over a day with less “off” time, he said, “but improvement in the best on' states have not been observed in most cases.”


In an open-label study designed to assess the safety and tolerability of escalating doses of aromatic L-amino acid decarboxylase (AADC) – an enzyme that converts levodopa into dopamine – he and his co-investigators infused the gene encoding for the agent into the putamen bilaterally in patients with moderate-to-advanced disease.

The investigators evaluated the patients at baseline and then monthly for six months, using the Unified Parkinson Disease Rating Scale (UPDRS), motor state diaries, and pre- and post-surgery PET with 6-[18F] fluoro-L-meta-tyrosine (FMT). They selected this tracer over fluorodopa because it has more specificity for AADC activity.


Dr. William J. Marks, Jr.: “Were not there yet, but this is the first step [the injection of neurturin] to treatments with disease-modifying capabilities.”

Six-month data were available for three of the four patients who had no serious adverse effects, said Dr. Christine. The investigators plan to enroll a total of 15 patients. Typical adverse effects were transient headache and surgical site discomfort, he said. The first PET images showed at least a 15 percent increase in FMT activity. The patients' average baseline UPDRS scores were 41.3 for “off” and 16.2 for “on.” Postoperative visits showed no worsening of these scores, he said, noting also that the motor diaries showed that time in the slow or frozen state had decreased without an increase in levodopa dosage.

“If there's a better conversion of levodopa into dopamine, patients may achieve better motor function with lower levodopa doses,” he said.


In other research, UCSF Associate Professor of Neurology William J. Marks, Jr., MD, and co-investigators examined delivery of a trophic factor by means of a viral vector.

“We're not there yet, but this is the first step to treatments with disease-modifying capabilities,” he said. Dr. Marks received clinical research funding from Ceregene, a biotech company.

He and his co-investigators conducted a phase I study based on the concept of targeted delivery of the trophic factor neurturin by a viral vector to the putamen. The concept is based on earlier findings that neurturin supports the survival of dopaminergic neurons and prevents degeneration of nigrostriatal neurons.

The investigators recruited 12 patients with Parkinson disease of at least Hoehn/Yahr stage 3 with motor fluctuations. The patients were an average of 57 years old. They received intraputaminal injections of adeno-associated viral vector containing DNA that encoded neurturin. Administration was delivered along eight injections per hemisphere along mapped trajectories.

The investigators gave six patients a low dose, consisting of 2 x 1011 vector genomes, while six patients received a high dose, consisting of 8 x 1011 viral genomes.

“This is the first time this compound has been tested in humans and to date, there have been no serious adverse events,” he said. The first patient was treated in June 2005 and the last one began in March 2006. “No clinically significant changes in symptoms, signs, or laboratory values have occurred.” The most common adverse events were transient pain and swelling at the surgical sites, headache, transient dyskinesia, and nausea.

“We look forward to following these patients longer term, but based on the accumulating safety and tolerability data, coupled with an ongoing analysis of efficacy data, we are planning a phase II multicenter study for later in the year.”

He added that he and his co-investigators at UCSF and Rush Medical Center were intrigued by the potential that trophic factors for maintaining or improving the health of degenerating nigrostriatal neurons. “The problem in the past was delivery, by catheter or diffusely through the intraventricular system,” he said. “Both approaches lack the appropriate targeting required for delivering growth factor. We hope that the viral vector can target the appropriate regions of the brain and deliver the trophic factor for some time.”


“These are two early attempts to apply gene therapy for Parkinson disease,” said Anthony Lang, MD, in an interview. “Dr. Christine's report is preliminary but encouraging. The main thing Dr. Christine and co-investigators need to do is continue to show that the treatment is safe and continue to administer it.” Dr. Lang is the Director of the Division of Neurology at the University of Toronto in Ontario, Canada.

“The trial headed by Dr. Marks is an attempt to change the biology of the disease and alter its course,” he added. “Although the investigators only presented safety data, I think that's appropriate. This is an open-label trial, with all the limitations of surgical open-label trials. Therefore, the authors were wise to hold off comments on efficacy, and they were also clear that they want to have long-term follow-up before commenting on efficacy.”

Gene therapy in Parkinson disease is still weighted by concerns about long-term complications, such as the development of spontaneous off-period dyskinesias, Dr. Lang said. Therefore, in the study headed by Dr. Marks, investigators will need to determine whether the dyskinesias they observed were a complication of the treatment.

“To me, the most important thing is that, at this stage, these studies exist,” said Karl Kieburtz, MD, in a phone interview. Dr. Kieburtz is a Professor of Neurology, and Community and Preventive Medicine at the University of Rochester in New York.


Dr. Anthony Lang said that gene therapy in Parkinson disease is still weighted by concerns about long-term complications, such as the development of spontaneous off-period dyskinesias.

“The technology has developed so that you can put specific genes in the viral vectors, get approval for the trials, and get patients to consent to participate in them. There are probably 20 or 30 of the one million PD patients in North America who have participated in trials with the gene transfer approach, and nothing terrible has happened yet. That's quite a step forward. It's reassuring that there's been no major toxicity reported.”

If these treatments are well-tolerated and the investigators get a sense that there is targeted effect, the next step in both cases would be randomized phase II studies with larger patient populations to see whether the gene is having its intended effect. “If in a larger group you're starting to see the desired impacts on disease features, the next step would be efficacy studies or Phase III studies,” he said.


  • ✓ Gene therapy for Parkinson disease was well-tolerated in two different trials – one involving escalating doses of aromatic L-amino acid and the other, involving intraputaminal injections of adeno-associated viral vector containing DNA that encoded neurturin.