Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC

doi:doi:10.1016/j.ymthe.2006.05.005

Molecular Therapy (2006) 14, 564–570; doi: 10.1016/j.ymthe.2006.05.005

Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC

Krystof S. Bankiewicz¹, John Forsayeth¹, Jamie L. Eberling², Rosario Sanchez-Pernaute³, Philip Pivirotto¹, John Bringas¹, Peter Herscovitch³, Richard E. Carson³, William Eckelman³, Bryan Reutter² and Janet Cunningham¹

¹Department of Neurosurgery, University of California at San Francisco, Room MCB 226, 1855 Folsom Street, San Francisco, CA 94103-0555, USA
²Center for Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
³Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA

Correspondence: Krystof S. Bankiewicz, E-mail: krystof.bankiewicz@ucsf.edu.

Received 19 March 2006; Revised 1 May 2006; Accepted 1 May 2006.

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Abstract

Dopamine, the major neurotransmitter depleted in Parkinson disease, can be synthesized and regulated in vivo with a combination of intrastriatal AAV-hAADC gene therapy and administration of the dopamine precursor L-Dopa. When tested in MPTP-lesioned monkeys, this approach resulted in long-term improvement in clinical rating scores, significantly lowered L-Dopa requirements, and a reduction in L-Dopa-induced side effects. Positron emission tomography with [¹⁸F]FMT confirmed persistent AADC activity, demonstrating for the first time that infusion of AAV vector into primate brain results in at least 6 years of transgene expression. AAV-hAADC restores the ability of the striatum to convert L-Dopa into dopamine efficiently. Introduction of this therapy into the clinic holds promise for Parkinson patients experiencing the motor complications that result from escalating L-Dopa requirements against a background of disease progression.