A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector–mediated gene delivery of aromatic L-amino a...

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Bibliographic Details
Published in:Molecular therapy 2010-09, Vol.18 (9), p.1731-1735
Main Authors: Muramatsu, Shin-ichi, Fujimoto, Ken-ichi, Kato, Seiya, Mizukami, Hiroaki, Asari, Sayaka, Ikeguchi, Kunihiko, Kawakami, Tadataka, Urabe, Masashi, Kume, Akihiro, Sato, Toshihiko, Watanabe, Eiju, Ozawa, Keiya, Nakano, Imaharu
Format: Article
Language:English
Subjects:
Aged
Amino acids
Aromatic-L-Amino-Acid Decarboxylases - genetics
Aromatic-L-Amino-Acid Decarboxylases - metabolism
Dopamine
Drug dosages
Drug therapy
Enzymes
Female
Gene therapy
Genetic Therapy - methods
Humans
Male
Medicine
Middle Aged
Neurology
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson Disease - therapy
Parkinson's disease
Patients
Positron-Emission Tomography
Surgery
Treatment Outcome
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Summary:Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector–mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[18F]fluoro-L-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2010.135