Gene therapy trial for parkinson's disease effective in improving motor function

Gene therapy trial for parkinson's disease effective in improving motor function

Parkinson's disease patients who have not responded to drug treatment experienced considerable improvement in motor function with injections of the GAD (glutamic acid decarboxylase) gene directly into their brains. The findings of this randomized, double-blind gene therapy trial have been published in the latest issue of The Lancet Neurology.

The authors wrote that further development of their gene therapy must be supported. They added that their trial highlights the potential of gene therapy for the treatment of signs and symptoms of several different brain disorders.

This is the first randomized double-blind trial to confirm the effectiveness of gene therapy, the researchers said.

GABA, a chemical involved in coordinating movement, is present in abnormally low levels in the subthalamic nucleus (a part of the brain) of individuals with Parkinson's disease.

In this new approach, scientists have developed a gene transfer therapy aimed at "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)."

The potential of this approach was demonstrated in a previous Phase I open-label trial. It had yet to be confirmed in a randomized double-blind trial.

Andrew Feigin from The Feinstein Institute for Medical Research, New York, USA, and team set up a double-blind randomized trial to determine what the effect might be if they delivered the GAD-bearing AAV2 into the subthalamic nucleus of 22 volunteers, compared to 23 individuals in a control group (sham surgery, placebo-like surgery). For a period of six months after surgery, the researchers used the UPDRS (Unified Parkinson's Disease Rating Scale) to gauge motor function of all 45 patients - assessments were carried out at regular intervals.

None of the patients died from surgery. The most common mild side-effects were nausea and headache, all of which were treated and resolved.

At the end of the six month monitoring and assessing period, the scientists report that:

  • There was a 21.3% improvement in UPDRS motor scores in the gene therapy patients
  • There was a 12.7% improvement in the control group
  • The gene therapy group also showed considerable improvements in resistance to drug control in advanced Parkinson's disease
The researchrs concluded:

"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."

Michael Hutchinson from New York University School of Medicine, New York, USA wrote in an Accompanying Comment:

"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.

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?"

"AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial"

Prof Peter A LeWitt MD, Prof Ali R Rezai MD, Prof Maureen A Leehey MD, Steven G Ojemann MD, Alice W Flaherty MD, Emad N Eskandar MD, Sandra K Kostyk MD, Karen Thomas DO, Atom Sarkar MD, Mustafa S Siddiqui MD, Prof Stephen B Tatter MD, Jason M Schwalb MD, Kathleen L Poston MD, Jaimie M Henderson MD, Prof Roger M Kurlan MD, Irene H Richard MD, Lori Van Meter MS, Christine V Sapan PhD, Prof Matthew J During MD, Michael G Kaplitt MD, Dr Andrew Feigin MD

The Lancet Neurology, Early Online Publication, 17 March 2011


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Section Issues On Medicine: Disease