A randomised, double-blind gene therapy trial for Parkinson's disease has shown that injection of the glutamic acid decarboxylase (GAD) gene directly into the brain is safe and can significantly improve motor function in patients who are not responsive to drug treatment. These findings, published Online First in The Lancet Neurology, support the further development of this state-of-the-art treatment for Parkinson's disease and highlight the potential of gene therapy to alleviate the symptoms of other brain disorders.
Despite promising results from several open-label studies of gene therapy, until now, none have been confirmed in subsequent randomised double-blind trials.
Patients with Parkinson's disease have substantial reductions in the amount of GABA (a chemical responsible for coordinating movement) in an area of the brain called the subthalamic nucleus. In a new approach to treating Parkinson's disease, researchers have developed a gene transfer therapy with the aim of increasing GABA production and restoring motor function by inserting the GABA-producing GAD gene into the subthalamic nucleus using a harmless form of adeno-associated viral vector (AAV2). This approach has shown potential in a previous phase 1 open-label trial, but has yet to be verified in a randomised double-blind trial.
Andrew Feigin from The Feinstein Institute for Medical Research, New York, USA, and colleagues designed a double-blind randomised trial to examine the effect of delivering the GAD-bearing AAV2 into the subthalamic nucleus (22 patients) compared with sham surgery (23 patients). The Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess the motor function of all patients at regular intervals up to 6 months after surgery.
All patients survived the surgery and had only mild side-effects related to the treatment that resolved; the most common were headache and nausea.
Significant improvements in motor scores were observed in gene therapy patients in the off-medication state (when patients had been off their medicines for 12 hours). At 6 months after surgery, patients in the gene therapy group had an average 23.1% improvement in UPDRS motor score compared with 12.7% in the placebo group.
Interestingly, patients given gene therapy also showed improvements in other clinical assessments of their main motor symptoms, particularly those resistant to drug control in advanced Parkinson's disease.
The authors conclude: "The use of somatic-cell gene transfer to alter gene expression in well characterised brain neurochemical systems offers a novel alternative to conventional pharmacological or surgical treatment. This study...justifies the continued development of AAV2-GAD for treatment of Parkinson's disease…and shows the promise of gene therapy for other neurological disorders."
In a Comment, Michael Hutchinson from New York University School of Medicine, New York, USA says: "There is hidden value to this meticulous study: it confirms that although a sustained placebo effect can be associated with surgery (12.7%), it is not of sufficient magnitude to explain the large beneficial effects detected in open-label surgical trials."
However, he adds: "Several questions remain. How long will the effect last? Will untoward long-term effects arise after the introduction of viruses into the brain? Does the technique offer any advantages over deep brain stimulation, for which clinical improvements seem twice as large?"
Dr Andrew Feigin, The Feinstein Institute for Medical Research, New York, USA. T) +1 516 562 2498 E) afeigin@nshs.edu
Dr Michael Hutchinson, New York University School of Medicine, New York, USA. Currently in Tokyo but contactable on T) +81 44 877 4321 E) Michael.hutchinson@nyumc.org
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The Lancet Neurology