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Results from a phase I safety trial of hAADC gene therapy for Parkinson disease

From the Department of Molecular Imaging and Neuroscience (J.L.E., W.J.J.), Lawrence Berkeley National Laboratory, Berkeley, CA; Department of Neurology (J.L.E.), University of California, Davis, CA; University of California (W.J.J.), Berkeley, CA; and Departments of Neurology (C.W.C., M.J.A.) and Neurological Surgery (P.S., P.L., K.S.B.), University of California, San Francisco, CA.

Address correspondence and reprint requests to Dr. Jamie L. Eberling, Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Mail Stop 55-121, Berkeley, CA 94720 jleberling{at}lbl.gov

Background: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients.

Methods: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression.

Results: PET results showed an average 30% increase in FMT uptake (K_i^c) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult.

Conclusions: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

GLOSSARY: AADC = aromatic l-amino acid decarboxylase; AAV = adeno-associated viral; DA = dopamine; FMT =6-[18F]fluoro-l-m-tyrosine; hAADC = human aromatic l-amino acid decarboxylase; l-dopa = levodopa; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

e-Pub ahead of print on April 9, 2008, at www.neurology.org.

Financial support for the clinical study and clinical trial material were provided by Genzyme Corporation, Cambridge, MA.

Disclosures: J.L.E.: Some of J.L.E.’s salary support has been derived from contracts with Genzyme to the Lawrence Berkeley National Laboratory. J.L.E. is also an inventor on a relevant patent (6309634). W.J.J. has no disclosures. C.W.C.: Some of C.W.C.’s salary support has been derived from the contracts with Avigen and more recently Genzyme to the University of California, San Francisco. C.W.C. has no other potential conflicts of interest, including consultancies, stock ownership, honoraria, paid expert testimony, patent applications, and travel grants, within the past 3 years. P.S.has no disclosures. P.L. has no disclosures. K.S.B. has potential conflicts of interest: is an inventor on a relevant patent (6309634) and was a consultant to Genzyme, the sponsor of the clinical trial. M.J.A.: The study was supported by Avigen and then by Genzyme, but M.J.A. has no financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work.

Received October 11, 2007. Accepted in final form February 14, 2008.

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