You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.
Note: You can also watch Dr. Okun address this topic in a video appearing at the end of this blog entry.
Hailed as a major breakthrough for Parkinson’s disease research, investigators from multiple institutions throughout the United States published an important paper on gene therapy in March 2011. The study was a double-blind (neither the investigators nor the patients knew which patients were receiving the real treatment) randomized trial, and was one of the largest of its type to be performed in actual Parkinson’s disease patients. The study utilized a clever and novel technology in order to change the nature of a nucleus in the brain called the subthalamic nucleus, which in PD becomes overactive leading to the movement disorders characteristic of the condition. The nucleus normally infuses excitatory chemicals into the brain, but was converted to infuse inhibitory chemicals. The investigators accomplished their goal by utilizing gene transfer of glutamic acid acid decarboxylase, or GAD into the subthalamic nucleus region. This technique was performed on two sides of each participant’s brain, and some patients received a sham surgery (a mock procedure designed to mimic the experimental approach). Although the results were not as robust as what has been observed with deep brain stimulation and with other therapies, the door seems to have swung open for gene therapy approaches in Parkinson’s disease.
The study included patients between the ages of 30 and 75 years who had a diagnosis of Parkinson's disease, and a very good response to levodopa therapy. Seven centers participated from across the United States. The study used a novel technology to apply gene therapy at the bedside, rather than in an operating room setting. Motor scores on a scale called the UPDRS were used as the primary outcome. Sixty-six patients were included in the study, and 23 were assigned to receive sham surgery and 22 assigned to gene therapy infusion. What is interesting about this study was that the investigators designed a completely sham procedure in order to be sure that there was a difference between the gene therapy group, and the sham operated group. The motor scores improved by eight points in the gene therapy group, and by nearly 5 points in the sham group. This was a significant difference favoring the gene therapy group. Only 21 sham surgery patients and 16 gene therapy patients of the original 66 were analyzed for primary outcomes meaning that the study was smaller than one may have hoped for. Importantly, the adverse event and safety profile were reported as excellent, with the most common side effect being headache (seven patients in the gene therapy group and only two in the sham group complained of this symptom). The study authors felt that this therapy should be further explored for Parkinson’s disease.
Though the results of this study were positive, patients should not come away with false impressions and with false hopes. This type of gene therapy was targeted as a symptomatic approach to address levodopa responsive Parkinson's disease issues. It was not a neuroprotective approach, nor was it a disease modifying approach. The benefits were mainly mild improvements in the motor symptom scale. Though the therapy fared better than sham, it did not perform better than deep brain stimulation performed in the same target (as reported by other recent studies).
The future of gene therapy for Parkinson's disease we hope will be bright. The lessons from early studies such as the one published in Lancet Neurology should point us in the right direction. Larger numbers of patients will need to be examined, outcomes optimized, and safety documented. There is an overriding concern for the future of gene therapy in long-term delayed adverse events, and we will need to carefully document their presence or absence. The transplant trials in Parkinson’s disease patients taught us important lessons including the appearance of delayed complications, one of which runaway dyskinesia, proved to be a limiting issue for continuation of the therapy.
Hopefully gene therapy approaches can be modified to address non-medication responsive symptoms of Parkinson's disease. Remember, this current gene therapy approach was aimed at achieving symptomatic improvement of levodopa responsive Parkinson's disease symptoms. The field remains however, in desperate need of therapies targeting both motor and non-motor symptoms that are resistant to levodopa and other therapies. These symptoms include but are not limited to walking, balance, speech, swallowing, cognition, mood, and sexual dysfunction.
We remain very encouraged about gene therapy and its possibilities for future use in Parkinson’s disease patients. This study will hopefully help to open some doors and to challenge our scientists to continue to develop and to continue to refine techniques that will target the symptoms that matter the most to our patients with Parkinson disease, mainly the levodopa resistant symptoms.
Lewitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind,sham-surgery controlled, randomised trial. Lancet Neurol. 2011 Mar 16. [Epub ahead of print] PubMed PMID: 21419704.