title: Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.
abstract: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion.
  
  
  
  Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day.
  
  
  
  All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable.
  
  
  
  The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD.
  
  
  
  ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Helga
authors.initials: H
authors.lastname: Eyjolfsdottir
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksdotter
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Neurosurgery, Karolinska University Hospital Solna, Building R3:02, 171 76, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Linderoth
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Neurosurgery, Karolinska University Hospital Solna, Building R3:02, 171 76, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Lind
authors.affiliation: NsGene Inc., 225 Chapman Street, Providence, RI, 02905-4533, USA.
authors.forename: Bengt
authors.initials: B
authors.lastname: Juliusson
authors.affiliation: NsGene Inc., 225 Chapman Street, Providence, RI, 02905-4533, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Kusk
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Ove
authors.initials: O
authors.lastname: Almkvist
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Clinical Neuroscience, University of Gothenburg, 41345, Gothenburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
authors.affiliation: Department of Laboratory Medicine, Section of Pathology, Karolinska University Hospital, 171 76, Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Karami
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Ahmadul
authors.initials: A
authors.lastname: Kadir
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Stiftelsen Stockholms Sjukhem, Mariebergsgatan 22, 112 35, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Sundström
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Wahlund
authors.affiliation: Department of Surgical Sciences, Section of Nuclear Medicine and PET, Uppsala University Hospital, 75185, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Wall
authors.affiliation: Department of Clinical Science, Intervention and Technology, Division of Medical Imaging and Technology, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Radiology, Karolinska University Hospital, 171 76, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Wiberg
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Department of Geriatrics, Karolinska University Hospital, Huddinge, 171 76, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|Stiftelsen Stockholms Sjukhem, Mariebergsgatan 22, 112 35, Stockholm, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Seiger
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77, Stockholm, Sweden.|NsGene Inc., 225 Chapman Street, Providence, RI, 02905-4533, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Wahlberg
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden. per.almqvist@ki.se.|Department of Neurosurgery, Karolinska University Hospital Solna, Building R3:02, 171 76, Stockholm, Sweden. per.almqvist@ki.se.
authors.forename: Per
authors.identifier: 0000-0002-0383-8189
authors.initials: P
authors.lastname: Almqvist
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D066187:Basal Forebrain / Q000000981:diagnostic imaging / Q000187:drug effects*; D002214:Capsules; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000134:cerebrospinal fluid; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D002214:Capsules; C502240:NGF protein, human; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase
keywords: Alzheimer’s disease; Encapsulated cell biodelivery; Nerve growth factor; Regenerative medicine