title: Safety and tolerability of putaminal AADC gene therapy for Parkinson disease.
abstract: BACKGROUND
  In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.
  
  
  METHODS
  Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression.
  
  
  RESULTS
  The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.
  
  
  CONCLUSIONS
  This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143-0114, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Christine
authors.forename: P A
authors.initials: PA
authors.lastname: Starr
authors.forename: P S
authors.initials: PS
authors.lastname: Larson
authors.forename: J L
authors.initials: JL
authors.lastname: Eberling
authors.forename: W J
authors.initials: WJ
authors.lastname: Jagust
authors.forename: R A
authors.initials: RA
authors.lastname: Hawkins
authors.forename: H F
authors.initials: HF
authors.lastname: VanBrocklin
authors.forename: J F
authors.initials: JF
authors.lastname: Wright
authors.forename: K S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: M J
authors.initials: MJ
authors.lastname: Aminoff
mesh_terms: D000368:Aged; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics* / Q000627:therapeutic use*; D015331:Cohort Studies; D020820:Dyskinesias / Q000503:physiopathology / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D020300:Intracranial Hemorrhages / Q000209:etiology; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures / Q000009:adverse effects; D010300:Parkinson Disease / Q000503:physiopathology* / Q000601:surgery / Q000628:therapy*; D049268:Positron-Emission Tomography; D011699:Putamen / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000601:surgery; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001142:Aromatic-L-Amino-Acid Decarboxylases