title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.
  
  
  BACKGROUND
  Oxford BioMedica.
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France. Electronic address: stephane.palfi@hmn.aphp.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Palfi
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Gurruchaga
authors.affiliation: Oxford BioMedica, Oxford, UK.
authors.forename: G Scott
authors.initials: GS
authors.lastname: Ralph
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Lepetit
authors.affiliation: CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.
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authors.lastname: Lavisse
authors.affiliation: John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.
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authors.initials: PC
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authors.affiliation: John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Colin
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authors.lastname: Watts
authors.affiliation: Oxford BioMedica, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Miskin
authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.lastname: Deeley
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Iwamuro
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Jean Pascal
authors.initials: JP
authors.lastname: Lefaucheur
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Claire
authors.initials: C
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; INSERM U955, E01, Institut de Recherche Biomédicale, Créteil, France.
authors.forename: Gilles
authors.initials: G
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Pierre
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Inanna
authors.initials: I
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Kou
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
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authors.affiliation: CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
authors.forename: Philippe
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authors.lastname: Le Corvoisier
authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.
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authors.affiliation: John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.
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authors.affiliation: John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.
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authors.affiliation: Gene Therapy, Centre of Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Hammersmith Hospital Campus, London, UK.
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: CIC9302 and UMR 825, INSERM and Department of Pharmacology and Neurosciences, University Hospital and University of Toulouse III, Toulouse, France.
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.
authors.forename: Philippe
authors.initials: P
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authors.affiliation: AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; INSERM U955, E01, Institut de Recherche Biomédicale, Créteil, France.
authors.forename: Pierre
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authors.affiliation: Oxford BioMedica, Oxford, UK.
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mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004296:Dopa Decarboxylase / Q000235:genetics; D004298:Dopamine / Q000096:biosynthesis; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000821:virology; D005500:Follow-Up Studies; D006136:GTP Cyclohydrolase / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000628:therapy*; D011699:Putamen; D014162:Transfection / Q000379:methods*; D019076:Transgenes / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics
chemical_list: D000978:Antiparkinson Agents; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase; D004296:Dopa Decarboxylase; D004298:Dopamine