BACKGROUND: Parkinson's disease is typically treated with oral dopamine 
replacement therapies; however, long-term treatment leads to motor complications 
and, occasionally, impulse control disorders caused by intermittent stimulation 
of dopamine receptors and off-target effects, respectively. We aimed to assess 
the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of 
ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and 
continuous dopamine production in patients with advanced Parkinson's disease.
METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at 
two study sites (France and UK) to assess the safety and efficacy of ProSavin 
after bilateral injection into the putamen of patients with Parkinson's disease. 
All patients were then enrolled in a separate open-label follow-up study of 
long-term safety. Three doses were assessed in separate cohorts: low dose 
(1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose 
(1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years 
or longer, motor fluctuations, and 50% or higher motor response to oral 
dopaminergic therapy. The primary endpoints of the phase 1/2 study were the 
number and severity of adverse events associated with ProSavin and motor 
responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part 
III (off medication) scores, at 6 months after vector administration. Both 
trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439.
FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, 
six mid dose, six high dose). During the first 12 months of follow-up, 54 
drug-related adverse events were reported (51 mild, three moderate). Most common 
were increased on-medication dyskinesias (20 events, 11 patients) and on-off 
phenomena (12 events, nine patients). No serious adverse events related to the 
study drug or surgical procedure were reported. A significant improvement in 
mean UPDRS part III motor scores off medication was recorded in all patients at 
6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 
27 [8]; n=15, p=0·0001) compared with baseline.
INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced 
Parkinson's disease. Improvement in motor behaviour was observed in all 
patients.
FUNDING: Oxford BioMedica.