Michael J. Aminoff, MD, DSc, FRCP, FAAN, Professor of Neurology and Director of the Parkinson's Disease Clinic & Research Center at the University of California San Francisco, discusses his paper "Safety and tolerability of putaminal AADC gene therapy for Parkinson Disease," recently published in Neurology® (2009:73;1662-1669). He spoke with José G. Merino, MD, MPhil, Science Editor of AAN.com.
AAN.com: Can you summarize the methodology and major findings of your study?
Aminoff: We infused an adeno-associated viral vector containing the gene for amino acid decarboxylase (AADC) into the putamen of 10 patients with advanced Parkinson's disease. In such patients, the normal level of striatal AADC declines with loss of the nigrostriatal nerve terminals, leading to a diminished ability to convert levodopa to dopamine. By our gene therapy, we hoped to restore the ability to make this conversion and thereby lead to symptomatic benefit.
Our study was a phase I study and thus focused primarily on safety of the approach. At six months, there was clinical improvement in the off- and on-medication states of our patients, but the lack of a placebo group means we have to interpret the result cautiously. Our approach involved PET scanning with a tracer specific for AADC, and this provided evidence of dose-dependent gene expression.
AAN.com: How do the striatal neurons incorporate the gene, and what is the role of the viral vector?
Aminoff: The viral vector was adeno-associated virus type 2 (AAV-2), which has no known pathogenicity in humans. The human AADC gene was incorporated within it. This was then injected into the striatum (putamen) where it was taken up selectively by neurons (as opposed to glia). It carried the human gene for AADC into the striatal neurons. Experiments in nonhuman primates by my colleague, Krys Bankiewicz, MD, PhD, professor of Neurosurgery and Neurology here at UCSF, have convincingly demonstrated such uptake and shown that this provided meaningful therapeutic benefit in animals with experimentally induced parkinsonism.
AAN.com: What were the characteristics of the patients included in your study?
Aminoff: My colleague, Chadwick W. Christine, MD, and I selected non-demented patients with Parkinson's disease, most of whom were attending our specialty clinic at UCSF. They had moderately severe parkinsonism (stage III to IV on the Hoehn and Yahr scale) and intractable motor fluctuation on dopaminergic therapy. They would have been candidates for deep-brain stimulation but volunteered for our study instead. They ranged in age from 57 to 71, with an equal gender distribution.
AAN.com: Please briefly describe the infusion procedure. What are the surgical risks?
Aminoff: Two cannulae were placed on each side in the postcommissural putamen and used to infuse the vector (50 microliters per site) at a rate of one microliter per minute. The cannulae were specially designed by Dr. Bankiewicz to optimize delivery without reflux ("convection-enhanced delivery"). Patients were usually awake for the procedure and tolerated it well. The risks of craniotomy include infection (which did not occur in our patients) and hemorrhage. Intracranial bleeding, found incidentally on postoperative MRI, occurred in two asymptomatic patients. One symptomatic patient who suffered a transient hemiplegia, was also found to have intracranial bleeding; he made an excellent recovery.
AAN.com: All subjects in your study showed improvement in the total Unified Parkinson's Disease Rating Scale (UPDRS), both in the off- and on-states. Was this change clinically meaningful?
Aminoff: This change was clinically meaningful as patients were in an "on-state" for longer, and therefore able to function more normally.
AAN.com: The patients also kept a motor state diary. What did the patient feel were the greatest effects of the therapy?
Aminoff: The greatest effect of the therapy from the patients' viewpoint was that they had reduced wearing off and felt improved for a longer period of time during the day. We did not find a dosage effect in clinical response (although such an effect was present on PET scan findings). We suspect that a higher dose than we used will lead to greater clinical effect, and we will test this in a future study. I should stress that since our study was not placebo controlled, we cannot be certain at this stage of a significant therapeutic effect due to the treatment.
AAN.com: In the PET studies you saw an increase in [18F]fluoro-l-m-tyrosine (an aromatic l-amino acid decarboxylase (AADC) tracer) uptake values in the putamen at one and six months in all patients, but the increase was greater for patients in the high dose group. What do these results tell you about the optimal dose? Did you find an association between dose and dyskinesias?
Aminoff: These issues have been the subject of endless discussion between Drs. Christine and Bankiewicz, and myself. We believe that a higher dose may lead to greater benefit—we will test this possibility in a future study. We did not see a definite association between dose and the occurrence of dyskinesia. It may well be that higher doses lead to more dyskinesia, but the beauty of our approach is that we can then reduce the level of levodopa medication and thus reduce dyskinesias. The occurrence of dyskinesias may in fact relate more to the distribution of AADC within the putamen than to the absolute dose used.
AAN.com: What are the potential risks of gene therapy and how do you minimize them?
Aminoff: In addition to the risks of the surgical procedure, which we discussed earlier, there are the risks of the viral vector itself. The AAV-2 vector seems completely safe and no complications attributable to it have been reported. Other viral vectors have led to such complications as oncogenesis or inflammatory responses.
AAN.com: Are higher doses more likely to promote an immune response, inflammation and neuronal damage, or be tumorogenic?
Aminoff: Unlike certain other viral vectors, this does not seem to be the case.
AAN.com: You describe two cohorts of a phase I study. Do you think your results support the design of phase II studies?
Aminoff: We firmly believe that a phase II study is now appropriate and such a study is planned, probably involving several sites.
AAN.com: What other gene therapies for PD are under evaluation?
Aminoff: A study involving the glutamic acid decarboxylase (GAD ) gene is currently underway. A phase II study of neurturin was recently completed but to my knowledge, the results have not yet been published. I can therefore not comment on this last study.
AAN.com: Do you anticipate that gene therapy will become a standard element of the armamentarium to treat PD in the next five to 10 years? What barriers (scientific, social, political) do you foresee?
Aminoff: Whether gene therapy becomes a standard treatment obviously depends on the outcome of these early studies. I am very optimistic about the future, if not with the genes that we have mentioned, then with other genes. Gene therapy, unlike deep-brain stimulation, does not require specialized programming and is not subject to complications such as device malfunction or the need for replacement of battery. It may also avoid complications that relate to pharmacological effects on widespread regions of the brain.
Within the past 24 months, Dr. Aminoff has received compensation as a consultant for iPerian, and has received royalties for chapters he authored for titles published by Elsevier and McGraw-Hill. In the same period, he received compensation for his service as Director of the American Board of Psychiatry & Neurology. He has served as series editor of the Handbook of Clinical Neurology (Elsevier). He has also served as an expert witness within the past 24 months. Dr. Aminoff has received research support from NIH, Avigen, Genzyme, and the Parkinson Study Group in the last five years.
Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates.