title: A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease.
abstract: BACKGROUND
  Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful.
  
  
  METHODS
  Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.
  
  
  RESULTS
  AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.
  
  
  CONCLUSIONS
  This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rafii
authors.affiliation: Ceregene, Inc., San Diego, CA, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Baumann
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Roy A E
authors.initials: RA
authors.lastname: Bakay
authors.affiliation: Ceregene, Inc., San Diego, CA, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Ostrove
authors.affiliation: Ceregene, Inc., San Diego, CA, USA.
authors.forename: Joao
authors.initials: J
authors.lastname: Siffert
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.affiliation: Ceregene, Inc., San Diego, CA, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Herzog
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Barba
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Pay
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Salmon
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.affiliation: Ceregene, Inc., San Diego, CA, USA.
authors.forename: Kathie
authors.initials: K
authors.lastname: Bishop
authors.affiliation: University of California, Irvine, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Keator
authors.affiliation: University of California, Irvine, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Potkin
authors.affiliation: Ceregene, Inc., San Diego, CA, USA. Electronic address: bartus@rtbioconsultants.com.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020532:Basal Nucleus of Meynert; D000229:Dependovirus / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000235:genetics*; D009483:Neuropsychological Tests; D019635:Neurosurgical Procedures; D049268:Positron-Emission Tomography; D013238:Stereotaxic Techniques; D016896:Treatment Outcome
chemical_list: C502240:NGF protein, human; D020932:Nerve Growth Factor
keywords: Cholinergic neurons; Gene therapy; Nerve growth factor; Neuroprotection; Neurorestoration; Neurotrophic factors; Nucleus basalis of Meynert; Translational R&D