Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial

Stéphane Palfi, Jean Marc Gurruchaga, G Scott Ralph, Helene Lepetit, Sonia Lavisse, Philip C Buttery, Colin Watts, James Miskin, Michelle Kelleher, Sarah Deeley, Hirokazu Iwamuro, Jean Pascal Lefaucheur, Claire Thiriez, Gilles Fenelon, Cherry Lucas, Pierre Brugières, Inanna Gabriel, Kou Abhay, Xavier Drouot, Naoki TaniAurelie Kas, Bijan Ghaleh, Philippe Le Corvoisier, Patrice Dolphin, David P Breen, Sarah Mason, Natalie Valle Guzman, Nicholas D Mazarakis, Pippa A Radcliffe, Richard Harrop, Susan M Kingsman, Olivier Rascol, Stuart Naylor, Roger A Barker, Philippe Hantraye, Philippe Remy, Pierre Cesaro, Kyriacos A Mitrophanous

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1138-46
Number of pages9
JournalThe Lancet
Issue number9923
Publication statusPublished - 29 Mar 2014

Keywords / Materials (for Non-textual outputs)

  • Aged
  • Antiparkinson Agents/administration & dosage
  • Dopa Decarboxylase/genetics
  • Dopamine/biosynthesis
  • Dopaminergic Neurons/metabolism
  • Follow-Up Studies
  • GTP Cyclohydrolase/administration & dosage
  • Genetic Therapy/adverse effects
  • Genetic Vectors/administration & dosage
  • Humans
  • Infectious Anemia Virus, Equine/genetics
  • Injections, Intralesional
  • Male
  • Middle Aged
  • Parkinson Disease/therapy
  • Putamen
  • Transfection/methods
  • Transgenes/genetics
  • Tyrosine 3-Monooxygenase/administration & dosage


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