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

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-mtyrosine (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.