Gene therapy may reverse Parkinson's disease symptoms

A novel therapy called NLX-P101, that involves surgical insertion of the gene for glutamic acid decarboxylase (GAD) and adeno-associated viral vector AAV2 into the brain, improved patients' motor scores on the unified Parkinson's disease rating scale (UPDRS) compared with placebo, study results published in Lancet Neurology indicate.

Many patients with Parkinson's disease become resistant to medical therapies that were once effective in the early stages of disease, or develop disabling side effects, according to background material in the study.

“Patients who received NLX-P101 showed a significant reduction in the motor symptoms of Parkinson's, including tremor, rigidity and difficulty initiating movement,” study researcher, Michael G. Kaplitt, MD, of New York Presbyterian Hospital and Weill Cornell Medical Center, both in New York City, said in a press release.

He and colleagues from several other U.S. sites, randomly assigned 45 patients with advanced Parkison's disease who were not adequately controlled with current therapy to receive either AAV2-GAD infusions (n=21) or sham surgery (n=16) in a phase-2 clinical trial to assess the efficacy of gene therapy six months after baseline.

Patients in the AAV2-GAD group received a bilateral infusion directly into the subthalamic nucleus, a key brain region involved in motor function, whereas patients in the sham surgery group underwent a procedure designed to make them believe that they had received the experimental therapy.

The researchers found that patients in the AAV2-GAD treatment group had a 23.1% improvement in UPDRS motor scores (8.1 point decrease; P<0.0001) compared with a 12.7% improvement in the sham surgery group (4.7 point decrease; P=0.003). Results were statistically significant during the entire six-month blinded study period (RMANOVA, P=0.04). Patients who experienced pump failures or inaccurate targeting of the subthalamic  nucleus were excluded from the analysis.

“Improved motor control was seen at one month and continued virtually unchanged throught the six-month study period,” Kaplitt said, adding that patients also report better medication control and no worsening in nonmotor symptoms.

The most common adverse events were headache (seven patients in the treatment group vs. two in placebo group) and nausea (six vs. two).

“This study was the first successful randomized, double-blind gene therapy trial for a neurological disorder and it justifies the continued development of AAV2-GAD for treatment of Parkinson's disease,” the researchers wrote.

A Larger clinical trial is still needed to confirm the results and determine whether treatment is practical for widespread clinical use.

Michael Hutchinson, MD, of New York University's Langone Medical Center praised the researchers for their care and “fastidiousness” in designing the study, as earlier trial results involving therapy with intraputemental infusion of glial-derived neurotrophic factor were inconclusive due to the placebo effects associated with surgery.  

 He also raised several questions for further study, including the long-term viability of benefits from the procedure, the possibility of adverse effects from introducing adenoviruses into the brain, and the advantage of NLX-P101 compared with existing therapies, such as deep brain stimulation.

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