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doi: 10.1097/01.NT.0000365667.39272.39
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A gene therapy that boosts production of dopamine in the striatum of patients with moderate Parkinson disease, as indicated by PET scan, also helped motor symptoms.

Patients with moderately advanced Parkinson disease (PD) who received an infusion of a gene therapy directly into the putamen bilaterally showed improved function on a rating scale, a change sustained beyond the six-month endpoint of the phase I safety study.

The therapy delivered the human gene for aromatic amino acid decarboxylase (AADC), the enzyme that produces dopamine from its precursor, levodopa.

“We know our gene transfer worked because of the PET scan results,” said investigator Michael Aminoff, MD, professor and executive vice chair in the Department of Neurology at the University of California-San Francisco. “We used a tracer specific for the gene product, aromatic amino acid decarboxylase, and showed a definite increase in signal that was dose-dependent.”

A placebo effect would not be dose dependent, Dr. Aminoff said.

As reported online Oct. 21 ahead of the print edition of Neurology, the investigators packaged the gene therapy with an adeno-associated viral vector for delivery into brain cells with an infusion cannula. At six months, PET showed a 30 percent increase of uptake of the AADC tracer [18]fluoro-L-m-tyrosine into the putamen in the low-dose cohort and a 75 percent increase in the high-dose cohort.

Collaborator Krystof Bankiewicz, MD, PhD, professor of neurosurgery and neurology and Kinetics Foundation Chair in Translational Research in Neurological Surgery at UCSF told Neurology Today: “For the first time we were able to distribute the vector effectively and produce a phenomenal increase as demonstrated by PET of a critical enzyme that can convert whatever little dopa these patients have, reducing the burden on the existing dopaminergic cells.”

Dr. Bankiewicz said PET studies have shown that degeneration of the dopamine nerve endings is uneven in PD patients, and most severe in the posterior striatum. As a result, the anterior areas are over-stimulated while patients are kept on dopaminergic medications. Adding the enzyme eases the metabolic stress on the remaining neurons, he said, so they no longer need to crank up production to compensate.

Japanese investigators will be publishing confirming data from six patients that these researchers studied, Dr. Bankiewicz said.



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Half of the ten patients received a low dose of the vector gene therapy and half a high dose. The researchers used the Unified Parkinson's Disease Rating Scale (UPDRS), which measures motor performance, cognitive deficits, and medication side effects. The test was given in the morning before patients took their first dose of levodopa, and again at the time that medication was most effective as rated by patient and physician. Testing was done at baseline and monthly for six months, and after the trial for patients who came for follow-up.

Among findings, combined data available for one and two years postoperatively showed continuing reductions in the total mean UPDRS scores (for five to seven patients): in the off-state, 37 percent at one year and 38 percent at two years, and at the on-state, 32 percent at one year and 22 percent at two years.

Dr. Bankiewicz said the improvements appear to exceed the effect of any study of a gene therapy in PD, or fetal cell implantation.

“We can regulate how effective this treatment is,” said Dr. Aminoff. “If we were to give too much, we could reduce the effect by lowering the dose of levodopa. We can thus adjust the effect of the gene therapy, and that is quite unlike any of the other gene therapies studied in patients with Parkinson disease.”

One patient had a significant neurological deficit resulting from an intracranial bleed, but recovered much of the lost function, said Dr. Aminoff. Two other patients had no clinical evidence of intracranial bleeds that had showed on MRI.

“It is a matter of concern that these hemorrhages occurred,” Dr. Aminoff said, adding that the study numbers were too small to know accurately the risk for this complication. He said investigators plan to modify the procedure to take less time for infusion of the vector and to change the trajectory of the infusion cannula, “and we will see how that works,” he said. A phase 2 trial is planned.

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Karl Kieburtz, MD, MPH, professor of neurology at the University of Rochester in New York, commented that the trial “is a very early phase I study that points out some of the issues of intracranial intervention. It is an open label study that was neither designed nor intended for efficacy, so the efficacy data need to be thought of in that context.”

Dr. Kieburtz said: “The intent of a phase I trial is to identify the safety and tolerability issues of such interventions. The impact on Parkinson disease is a different question, and one that is not able to be addressed rigorously without a comparison group.”

Michael Schlossmacher, MD, associate professor in the Division of Neurosciences at the University of Ottawa in Ontario, Canada, said the findings show that a gene therapy approach may be feasible for aspects of the disease, but he takes issue with the dopamine-centered approach of this and other efforts to devise a better treatment for Parkinson disease.

“Focusing on dopamine restoration is not going to fix the problem,” he said. Instead, investigators could target genes directly responsible in the development of the disease.

“One thing we've learned is that the treatment of motor aspects such as slowness, stiffness, tremor, and dyskinesia is not the biggest challenge down the road.”

When a patient is ten years into the disease, he said, “the unresolved issues are autonomic and cognitive problems. These are not primary dopamine deficiency issues.”



“For the motor complications of advanced PD, we already have deep brain stimulation,” Dr. Schlossmacher added.

“What is intriguing about this study,” he said, is that it showed feasibility for the chosen vector delivery protocol, provided the first insights concerning safety, and likely demonstrated efficacy regarding the expression of the protein of interest, all of which may have translated into improved UPDRS scores in the off and on states.

“It looks like a proof-of-principle study, but one has to be careful with the interpretation of the results until a proper placebo arm is included.”

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• Christine CW, Starr PA, Aminoff MJ, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009; E-pub 2009 Oct 21.
    • Kaplitt MG. Gene therapy clinical trials in the human brain. Protocol development and review of current applications. Front Neurol Neurosci 2009;25:180–188. E-pub 2009 Mar 19.
      • Manfredsson FP, Okun MS, Mandel RJ. Gene therapy for neurological disorders: challenges and future prospects for the use of growth factors for the treatment of Parkinson's disease. Curr Gene Ther 2009;9(5):375–388.
        ©2009 American Academy of Neurology