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Gene Therapy for PD Show Promise

Fitzgerald, Susan

doi: 10.1097/01.NT.0000397958.19762.29
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Patients who received a bilateral infusion into the subthalmic nucleus of a vector carrying the gene for glutamic acid decarboxylase (GAD) scored significantly better on a rating scale of motor function six months after treatment compared with patients who underwent sham surgery that was designed to mimic the gene treatment.

New findings from a randomized, double-blind trial of gene therapy for Parkinson disease (PD) provide a strong indication that the approach could be helpful for PD patients.

Patients who received a bilateral infusion into the subthalmic nucleus of a vector carrying the gene for glutamic acid decarboxylase (GAD) scored significantly better on a rating scale of motor function six months after treatment compared with patients who underwent sham surgery that was designed to mimic the gene treatment.

“This study was the first successful randomized, double-blind gene therapy trial for a neurological disorder (panel) and it justifies the continued development of AAV2-GAD for treatment of Parkinson's disease,” the researchers concluded in a report published March 16 in the online edition of The Lancet Neurology.

An editorial that accompanied the published findings noted that the phase 2 gene therapy trial was carefully designed and executed. “The main result was a mean improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the treatment group of 23.1% at 6 months, compared with 12.7% in the placebo group; the difference between the groups was significant when compared across the 6-month double-blind period,” wrote the editorialist Michael Hutchinson, MD, associate professor of neurology at New York University.

Andrew S. Feigin, MD, a co-principal investigator for the study, told Neurology Today that the study findings show that “the treatment was very safe and well tolerated.”

“We were also able to show that the promising results from a phase 1 trial could be confirmed in this more rigorous trial,” said Dr. Feigin, associate professor of neurology and molecular medicine at the Feinstein Institute for Medical Research at North Shore-LIJ Health System. Dr. Feigin, who also is a member of the Neurology Today editorial advisory board, said it was unlikely that gene therapy would prove useful for every PD patient, but he said the approach could add an important new tool to the lineup of treatment options.

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The study was carried out from November 2008 to May 2010 at seven medical centers in the US that specialize in PD care and functional neurosurgery. All patients recruited for the study had progressive, levodopa-responsive PD as defined by the UK Parkinson's Disease Society criteria. Study participants also were allowed to be taking other drugs for the disorder if no change in dose or medication type had been made at least four weeks before enrollment. All participants had an overnight off-medication UPDRS part 3 summed subscore (motor score) of 25 or more; were between the ages of 30 to 75; had symptoms of PD for at least five years; had been responsive to levodopa for at least a year; and had good cognitive function. Patients underwent 18F-fluorodeoxyglucose PET scans to confirm that they had metabolic brain activity typical of PD.

Of 66 patients assessed for eligibility, 45 were randomized into the trial, 23 receiving AAV2-GAD infusions and 22 getting sham surgery. Because all the patients were awake during surgery, the operating room teams practiced a routine so that the sham surgery looked and sounded like the real thing. The patients‘ baseline UPDRS scores were then compared to their follow-up scores during the six-month course of the study. Some patients were excluded from the primary analysis before study unblinding because they received incomplete treatment due to technical problems, leaving 37 patients in the analysis.

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AAV2-GAD treatment led to an improvement of 8.1 in off-medication UPDRS motor score at the study endpoint of six months, compared with 4.7 with sham treatment, the researchers reported. Fifty percent of the patients in the gene therapy group had an improvement of at least 9 points, which is considered significant, compared to 21 percent of the sham surgery patients. Some secondary measures also suggested that the gene therapy was doing some good.

For example, the investigators‘ clinical global impression of PD severity showed significant improvement at six months compared with baseline, according to the report. “The off-medication global rating of parkinsonism provided by a masked rater at every study visit showed differences between groups in changes from baseline at 1, 3 and 6 months.” No significant differences between the groups were noted in various secondary outcome measures at six months, including UPDRS activities of daily living, dyskinesia ratings, and measurements of off-state walking and tapping rates.

One patient in the gene therapy group experienced a serious adverse event — bowel obstruction — during the study period, but the problem was deemed unrelated to the surgery or the treatment. Headache and nausea were more common in the gene therapy group than among those who had sham surgery.

The authors noted that deep brain stimulation (DBS) targets the subthalmic nucleus, but the “technique necessitates implantation of devices and much effort to adjust electrical stimulation variables,” adding that gene therapy “may offer an alternative therapeutic strategy.”

Peter LeWitt, MD, another co-principal investigator for the study, told Neurology Today that the while the gene therapy was not tested against deep brain stimulation (DBS), it might provide a benefit comparable to that achieved with DBS. Dr. LeWitt, professor of neurology at Wayne State University, noted that DBS targets the subthalmic nucleus, and the infusion catheter the investigators used “has a volume about 40 times smaller than a typical electrode used in DBS.”

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But several experts, who were not involved with the current study, questioned the comparison to DBS and the authors‘ interpretation of the results.

The study was not designed to compare gene therapy to DBS, acknowledged Michael Okun, MD, associate professor of neurology at the University of Florida and medical director for the National Parkinson Foundation. But, he added, “the results, while positive, are not as strong as what's been seen in most deep brain stimulation trials.”

Although the safety profile emerging from the study was “better than expected…the efficacy of gene therapies will have to be improved to put them on the same plane as other available therapies,” Dr. Okun added.

“We‘re always looking for something hopeful to report for PD therapy, but we have to be realistic about the findings of this study,” said William J. Weiner, MD, professor and chair of the department of neurology at the University of Maryland School of Medicine in Baltimore, in a phone interview. “One can‘t be overly enthusiastic about these results. The data on the efficacy of the gene therapy, though statistically significant, were very modest at best in terms of producing a clinically significant change.”

Moreover, Dr. Weiner, who also serves on the editorial advisory board for Neurology Today, pointed out there were certain limitations in the study design. He noted that the investigators excluded from their analysis those patients who received incomplete treatment due to technical problems. “In a clinical trial, everyone in the treatment groups should be included in the ‘intent to treat‘ group — that's part of the study. To do otherwise, is to change the study design.”

Chadwick Christine, MD, associate professor of neurology at University of California-San Francisco, who was not involved with the study, told Neurology Today that this latest gene therapy study proved the technique can be done safely; but he described the results “as a positive finding with benefits that were modest in magnitude.”

Dr. Christine was part of another team that infused the gene for aromatic L-amino acid decarboxylase, an enzyme that converts levodopa into dopamine, into the putamen. The open-label study, reported in Neurology in November 2009, pointed to some benefit, and Dr. Christine said his team hopes to test the therapy further in a larger, randomized trial. The researchers who tested the AAV2-neurturin gene therapy are also still pursuing their approach.

The AAV2-GAD gene therapy is produced by Neurologix, Inc, a biotech company in Fort Lee, NJ. Matthew During, MD, who co-founded and serves as a consultant to Neurologix, said the company is in discussions with the FDA about conducting a phase 3 trial of the gene therapy as the next step toward gaining approval for marketing.



Dr. During, professor of molecular virology, immunology and medical genetics, neuroscience and neurological science at Ohio State University, said the study, still in the planning stage, would likely include 200 to 240 patients and involve a head-to-head comparison with either best medical therapy or sham surgery. Meanwhile, the patients in the current study are still being followed and “from our preliminary assessment it looks like the efficacy is maintained. We don‘t see any lack of efficacy over time,” Dr. During said. “We believe the gene effect is consistent. It stays in the cells and stays with the individual for life.”

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Lewitt PA, Rezai AR, Feigin A, et al. AAV2-GAD gene therapy for advanced Parkinson's disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 2011; E-pub 2011 Mar.16.
    Hutchinson M. Editorial: At last, a gene therapy for Parkinson's disease? Lancet Neurol 2011; E-pub 2011 Mar.16.
      Christine CW, Starr PA, Aminoff MJ, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009 73:1662-1669; E-pub 2009 Oct. 14.
        ©2011 American Academy of Neurology