NEWS IN CONTEXT: Phase 1 Safety Trial of Novel Gene Therapy for PD Reported Safe and Tolerable
On Friday, June 22, news outlets reported the publication in the journal Lancet of results from a Phase 1 trial conducted to determine the safety of a novel gene therapy approach to Parkinson’s. The trial, conducted in 12 patients, determined that the approach was safe, and researchers also reported that it seemed to improve PD symptoms without causing side effects.
The Michael J. Fox Foundation spoke to Thomas Wichmann, MD, associate professor of neurology at Emory University in Atlanta, Georgia, about how people with Parkinson’s should interpret the news.
Q: The researchers in this study targeted GAD. Can you give a little background on what we know about this gene?
TW: The abbreviation GAD stands for glutamic acid decarboxylase. This gene is needed for the brain to produce a compound called GABA, from a precursor molecule, glutamate. Glutamate is the major excitatory neurotransmitter in the brain, while GABA is the primary inhibitory transmitter.
It is known that certain areas of the brain are overactive in Parkinson’s disease. Introducing GAD into these regions in order to ramp up GABA production could be beneficial, because it may inhibit these regions to some extent. However, GAD is expressed in almost all regions of the brain; systemic drug treatments that would alter GAD activity (in general) would therefore be too non-specific. It is therefore a critical component of the study by Kaplitt et al. that an intervention was chosen that was aimed at increasing GAD production in a small portion of the brain that is known to be overactive in PD.
Q: Are there other existing PD interventions that target GAD?
TW: Although there are drugs in common use that target the GABA system in general (such as benzodiazepines), there are no specific existing therapies for PD that would target GAD. Other GAD-targeting gene therapy approaches (aimed at other brain regions) have been tried in parkinsonian animals, but these therapies have not reached the clinical trial stage.
Q: In the current study, the researchers injected GAD-AAV into the subthalamic nucleus, the same region of the brain that has been called the most effective region to target in DBS surgery. Is this more than a coincidence?
TW: This is not a coincidence at all. The subthalamic nucleus is a small and very dense region of the brain that was has shown to be overactive in animal models of Parkinson’s disease in the late 1980s. Lesioning studies showed that inactivation of this nucleus has profound effects on the parkinsonian movement abnormalities. Since that time, the nucleus has become one of the primary targets for neurosurgical interventions, such as deep brain stimulation (DBS) or lesions. These surgical techniques are aimed at reversing or limiting the overactivity of the subthalamic nucleus. The GAD-AAV approach has been developed in animal models as yet another method to reduce the overactivity in this brain region, with the hope that gene therapy that results in overproduction of the inhibitory transmitter GABA may accomplish this goal in a more gentle manner than the existing methods.
Q: Can patients who have undergone DBS of the subthalamic nucleus expect to experience similar effects to what would potentially be seen in this gene therapy treatment? If not, what are the added benefits that would lead a patient to seek out the gene therapy — were it to be approved — over the DBS procedure?
TW: It is too early to make any comparisons between the two techniques. DBS is a highly efficacious surgical technique to treat Parkinson’s disease. Given the very limited and preliminary data on the gene therapy approach, I would expect that the overall benefit that can be derived from the gene therapy will not exceed that of DBS, although it may differ in some of its effects and side effects.
From a practical point of view, the two therapy approaches differ substantially. DBS methods require that the patient is implanted with an electrode, and that stimulation parameters are periodically adjusted after the operation. Every few years, the battery that powers the stimulator needs to be exchanged. These specifics of DBS therapy imply that DBS brings with it the benefit that the therapy can be tailored to the patient’s needs after the implantation, and that the procedure is principally reversible (through removal of the device). These advantages come at the cost of complications such as electrode infections or malfunctions which occur in a small percentage of patients.
In contrast, the gene therapy approach is a one-shot procedure: The surgeon injects the solution containing the AAV virus with the GAD gene. Once in place, the therapy has the benefit that it does not need any specific follow-up, but it may have the disadvantage that it is not reversible or adjustable (in its current form). Surgical errors or complications from the therapy itself will be more difficult to correct.
Time will tell whether the two procedures differ in some of their effects and side effects. Both aspects are reasonably well established for the current DBS treatment, while this information is not available for the new gene therapy.
Q: What is the clinical perspective on the new findings and how should patients react to the news given that this was, at the end of the day, still only a phase 1 safety trial? How optimistic should people feel?
As you state correctly, this was a phase-1 safety trial. It had an unblinded, non-randomized, open-label design, as is often the case with safety trials. What this jargon really means is that the study was open to potential biases. The study was not designed (and therefore cannot) really inform us about the effectiveness of the new therapy.
It is, however, encouraging that the authors found that the therapy could be safely applied, and that no serious adverse events occurred during an observation period of more than three years in some of the patients. The apparent beneficial effects are also interesting, and should be reason to consider planning larger blinded and randomized studies to look at the true benefit of the therapy. Overall, I am cautiously optimistic regarding the use of this therapy. The question whether it will provide benefits beyond those of the existing pharmacologic and surgical treatments is completely open at this point.
In general, the new findings are significant, because they show that gene therapy can safely be done in Parkinson's disease. This may open the door not only to GAD-delivery approaches, but also to other gene therapies for Parkinson's disease.
Q: Is there anything we haven't covered that you feel people should keep in mind when it comes to this study?
TW: This study was carefully conducted. Specifically, the addition of imaging data was a very positive step. The imaging data showed that the therapy has effects that in some sense are similar to those of deep brain stimulation of the subthalamic nucleus.
There are a number of issues that I would have liked to see addressed in greater detail. One is the question whether the patients that were enrolled in this study had significant dyskinesias, and whether such involuntary movements changed with the treatment. Secondly, while the paper states that there were no changes in neuropsychiatric tests, the extent of the neuropsychiatric evaluations is not entirely clear from the text. Changes in cognition and mood occur as side effects of DBS therapy, and it will be interesting to find out in the future how the two treatment modalities compare in this regard. Finally, it would have been of interest to know how specific the treatment was. While the injections targeted the subthalamic nucleus, the injected volume was large enough to have potentially also affected neighboring areas. All of these questions will have to be addressed in the future.
