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Published online before print October 14, 2009, doi:10.1212/WNL.0b013e3181c29356)
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NEUROLOGY 2009;73:1662-1669
© 2009 American Academy of Neurology

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease

C. W. Christine, MD, P. A. Starr, MD, P. S. Larson, MD, J. L. Eberling, PhD, W. J. Jagust, MD, R. A. Hawkins, PhD, H. F. VanBrocklin, PhD, J. F. Wright, PhD, K. S. Bankiewicz, PhD and M. J. Aminoff, MD

From the Departments of Neurology (C.W.C., K.S.B., M.J.A.), Neurological Surgery (P.A.S., P.S.L., K.S.B.), and Radiology and Biomedical Imaging (R.A.H., H.F.V.), University of California, San Francisco, CA; The Michael J. Fox Foundation for Parkinson’s Research (J.L.E.), New York, NY; Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, and Helen Wills Neuroscience Institute (W.J.J.), University of California, Berkeley, CA; University of Pennsylvania School of Medicine (J.F.W.), Philadelphia, PA.

Address correspondence and reprint requests to Dr. Michael J. Aminoff, UCSF Department of Neurology, 505 Parnassus Ave., Room 795-M, San Francisco, CA 94143-0114 aminoffm{at}neurology.ucsf.edu

Background: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.

Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [18F]fluoro-l-m-tyrosine (FMT) were performed as a measure of gene expression.

Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.

Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Abbreviations: AADC = l-amino acid decarboxylase; AAV-hAADC = adeno-associated viral type 2 vector containing the human AADC gene; DA = dopamine; FMT = [18F]fluoro-l-m-tyrosine; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MSN = medium spiny neurons; NS = not significant; PD = Parkinson disease; UPDRS = Unified Parkinson’s Disease Rating Scale.

Supplemental data at www.neurology.org

e-Pub ahead of print on October 14, 2009, at www.neurology.org.

Disclosure: Author disclosures are provided at the end of the article.

Received May 1, 2009. Accepted in final form August 14, 2009.