Gene Therapy Trial Reports Improvements in PD Symptoms
On March 16, The Lancet Neurology published results from a randomized, controlled, double-blind phase II clinical trial of a novel gene therapy (NLX-P101) for Parkinson's disease. Subjects who received the therapy had an average 23 percent improvement in Parkinson's symptoms according to a widely used rating scale, versus an average of roughly 13 percent of those who did not receive the treatment.
The Michael J. Fox Foundation spoke with Irene Hegeman Richard, MD, Associate Professor of Neurology and Psychiatry at the University of Rochester School of Medicine and an author of the paper, to learn more about what the study results may mean for people with PD.
MJFF: Let's start with the basics -- can you explain what gene therapy is?
IR: Gene therapy involves giving patients a new gene that is intended to have a therapeutic effect. Usually, genes are transferred to patients with a viral vector.
MJFF: How is the gene in this particular therapy expected to help people with Parkinson's, and how is it different from other surgical treatments for PD?
IR: The researchers were studying a gene that makes an enzyme called glutamic acid decarboxylase (GAD). This enzyme helps produce a neurotransmitter called GABA, which is thought to quiet nerve cells in the subthalamic nucleus (STN) -- a region of the brain that is overactive in Parkinson's patients and plays a role in many PD symptoms. Because of the blood-brain barrier, surgery was required to deliver the GAD gene into the STN. The surgeon drilled a small hole in the skull, and the therapy was infused into the STN with a catheter. The treatment itself is named NLX-P101.
This approach is different from other surgical treatments for PD. In one treatment, surgeons create a lesion in the brain, which may reset brain activity to improve motor function. Another more commonly used surgical therapy, deep brain stimulation (DBS), involves placing electrodes into the STN to alter the activity of neurons in that region. The gene therapy in this study seeks to achieve the same goal as DBS using biology instead of an electrical stimulator. After DBS surgery, the system is turned on and adjustments to the stimulation parameters are typically made periodically. Unlike DBS, once the gene has been transferred to the patient, no further activities are required but there is also no opportunity for it to be "turned off."
MJFF: What were the major findings from this study?
IR: One major finding was to show that it is possible to conduct a well-controlled, safe surgery trial that produces reliable results. Randomized, double-blind clinical trials are the gold standard for evaluating the safety and effectiveness of medications, but they are less commonly done to test potential surgical treatments. However, it is as important to include a control group in surgery trials because there can be a large placebo response that makes it difficult to see whether or not the surgery is effective.
In this study, 45 subjects with advanced Parkinson's disease were randomized to get either NLX-P101 or "sham" surgery (the control group). Subjects in the control group went through a simulation mimicking a rigorous surgical procedure similar to that in the active treatment group. This was done because subjects were awake during surgery and it was important that they not know which group they were in. Similarly, the investigating clinicians who were responsible for evaluating the patients after surgery did not know which patients had the actual surgery and which patients had the "sham" surgery.
The primary outcome looked at changes in symptoms six months after the surgery, measured by the Unified Parkinson's Disease Rating Score (UPDRS). Overall, the average scores on the UPDRS were better (lower) for subjects who received NLX-P101 (8.1 points) than those in the "sham" surgery group (4.7 points). The difference was small but it was statistically significant.
In addition, half of the subjects who received NLX-P101 had a clinically meaningful improvement of nine points or greater, compared with just 14 percent of those in the placebo group.
The results did not reveal statistically significant improvements in quality of life or overall function, but this may have been due to the small sample size of the study. Importantly, the therapy did not cause many significant side effects.
As specified ahead of time in the research plan, subjects for whom the surgical delivery technique was not considered optimal (six in the gene therapy group, two in the control group) were excluded from the final analyses. The researchers did this because the goal of the study was to determine whether the therapy, when delivered appropriately, improved symptoms. The study results suggest that this is the case. However, additional work may be required to improve the delivery procedure for future clinical testing.
MJFF: The study looked at the effects of NLX-P101 over a six-month period. Would patients continue to derive benefit from this therapy beyond six months? Is there any risk linked to having a new gene inserted into the brain?
IR: That's an important question and one that the results of this study can't answer. The researchers are conducting an open-label, follow-up phase of this study to see if the benefits of NLX-P101 are sustained over time. The study will also monitor subjects for the emergence of long-term side effects. It is important to remember that, given current technology, once a gene is inserted into the brain it cannot be 'turned off." These long-term evaluations are critical.
MJFF: If it came to market, would NLX-P101 be appropriate for all people with Parkinson's disease?
IR: This study involved carefully selected patients with relatively advanced disease who were experiencing complications related to medication treatment. Therefore, this would be the type of patient for whom the therapy would be most appropriate. The therapy would have to be studied in other types of patients before being considered an appropriate treatment for them.
MJFF: Would this therapy radically transform the way we treat Parkinson's disease?
IR: The results of this particular study do not suggest that NLX-P101 will offer a radically transformative or disease-modifying therapeutic option. We clearly need larger trials to determine the degree to which this therapy may impact function and quality of life. However, this study shows that gene therapy may be an effective and safe option and that surgery trials can be performed well.
MJFF: Are any other types of gene therapy being studied?
IR: Right now, there are several gene therapies for Parkinson's disease in clinical trials. Most of these therapies aim to prevent neurons from dying or to increase dopamine production. Depending on the results of gene therapy studies, and how they compare with currently available therapies, it is possible that patients may have gene therapy as another treatment option sometime in the next several years.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.