title: Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains.
abstract: BACKGROUND
  AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc).
  
  
  METHODS
  We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated.
  
  
  RESULTS
  NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons.
  
  
  CONCLUSIONS
  These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved.
authors.affiliation: Ceregene Inc., San Diego, California 92121, USA. rtbartus@ceregene.com
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Herzog
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chu
authors.forename: Alistair
authors.initials: A
authors.lastname: Wilson
authors.forename: Lamar
authors.initials: L
authors.lastname: Brown
authors.forename: Joao
authors.initials: J
authors.lastname: Siffert
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Johnson
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
mesh_terms: D000368:Aged; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D051101:Neurturin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051101:Neurturin; D014446:Tyrosine 3-Monooxygenase