1. ¹Department of Neurosurgery, University of California at San Francisco, Room MCB 226, 1855 Folsom Street, San Francisco, CA 94103-0555, USA
2. ²Center for Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
3. ³Avigen, Inc., Alameda, CA 94502, USA

Correspondence: Krystof S. Bankiewicz, E-mail: kbank@itsa.ucsf.edu.

Received 4 January 2006; Revised 14 March 2006; Accepted 2 April 2006.

Abstract

The main medication for idiopathic Parkinson disease is L-Dopa. Drug efficacy declines steadily in part because the converting enzyme, aromatic L-amino acid decarboxylase (AADC), is lost concomitant with substantia nigra atrophy. Over the past decade, we have developed a gene therapy approach in which AADC activity is restored to the brain by infusion into the striatum of a recombinant adeno-associated virus carrying human AADC cDNA. We report here the results of an investigation of the relationship between vector dose and a series of efficacy markers, such as PET, L-Dopa response, and AADC enzymatic activity. At low doses of vector, no effect of vector was seen on PET or behavioral response. At higher doses, a sharp improvement in both parameters was observed, resulting in an approximate 50% improvement in L-Dopa responsiveness. The relationship between vector dose and AADC enzymatic activity in tissue extracts was linear. We conclude that little behavioral improvement can be seen until AADC activity reaches a level that is no longer rate limiting for conversion of clinical doses of L-Dopa into dopamine or for trapping of the PET tracer FMT. These findings have implications for the design and interpretation of clinical studies of AAV-hAADC gene therapy.