AAV-GAD Gene Therapy for Parkinson’s Symptoms

Dr. Jim Bennett, Center Director, shares his comments on the recent published findings of the AAV2-GAD gene therapy for advanced Parkinson’s disease trial.

In the April, 2011 issue of The Lancet-Neurology, results of a
double-blind, sham surgery controlled, Phase 2 study of gene therapy for Parkinson’s
disease symptoms were reported.

The study is compelling for several reasons:

  • This is the first Phase 2 study of gene therapy in Parkinson’s disease where a sham surgery was carried out as part of blinding the patients and evaluators. Patients in
    the sham surgery group received partial burr holes drilled into their skulls, and the surgical teams carried out a rehearsed, mock infusion. In this manner the sham surgery patients believed that they had received the active gene therapy, even though they had not. Only the surgical team knew of this ruse, which was very important in being able to decide whether the treatment worked or not.

  • Parkinson’s patients who participated were very carefully selected. Not only did
    they have typical exam findings and responses to L-DOPA, but they each underwent a special brain PET scan to measure patterns of glucose consumption rates. Their brain metabolism had to “look” like PD by this elaborate assay method.

  • Six months after they received sham surgery, PD subjects showed improvement in their PD symptoms after withdrawal from all medications. The important finding is that those who received actual delivery of the gene therapy virus showed more improvement that
    was statistically better compared to those receiving sham therapy. PD subjects
    consistently demonstrate this “placebo” effect that has been traced to increased release of remaining dopamine. By believing they received active treatment, those with PD release dopamine and are temporarily better. This phenomenon confounds studies of symptomatic therapies and requires elaborate methods to control for this effect.  

So what does this study mean?
First, it’s important to understand that the gene therapy injected attempted to increase production of an important neurotransmitter GABA
(gamma-amino butyric acid) in the subthalamic nucleus (STN). The STN is an important and frequently used targeting site for deep brain stimulation (DBS).
In earlier studies of DBS electrode placement into the STN, infusion of a chemical that mimics GABA improved parkinsonism signs, suggesting that increasing GABA function in STN might be helpful.

The gene therapy used a relatively benign virus, adeno-associated virus (AAV), to introduce the GAD gene into neurons. AAV is a mildly mannered cousin of adenovirus that causes much respiratory illness. AAV has become a popular virus to deliver genes to
human cells because it usually causes minimal problems by itself, yet it is capable of integrating the introduced gene into the genome of human cells. As long as the introduced gene is not chemically “silenced” by the host cell, it can continue to produce the desired product, which is this case are two closely related forms of the enzyme glutamic acid decarboxylase (GAD) that naturally manufactures GABA from the abundant amino acid glutamic acid.

Is this form of gene therapy more effective than DBS electrodes in the STN? That remains to be determined. For the moment, DBS electrode placement has become the standard of care for PD symptoms once they reach a certain level of difficulty in control. The Lancet
gene therapy paper demonstrates that presumed local increases in GABA formation
in STN could have similar beneficial effects. To find out which treatment is better for PD symptoms, much larger populations will need to be studied for longer periods of time, and the two treatments will have to be compared directly one to the other.

To obtain a copy of the full article, click here to be redirected to PubMed.

About aperseghin

Andrea Perseghin is the Associate Director for Education and Outreach at the VCU PMDC. She manages all of the educational programming for the center -- and is lost without her iPhone alerts.

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