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

Helga Eyjolfsdottir, Maria Eriksdotter, Bengt Linderoth, Göran Lind, Bengt Juliusson, Philip Kusk, Ove Almkvist, Niels Andreasen, Kaj Blennow, Daniel Ferreira, Eric Westman, Inger Nennesmo, Azadeh Karami, Taher Darreh-Shori, Ahmadul Kadir, Agneta Nordberg, Erik Sundström, Lars Olof Wahlund, Anders Wall, Maria WibergBengt Winblad, Åke Seiger, Lars Wahlberg, Per Almqvist*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)


Background: 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. Methods: 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. Results: 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. Conclusions: 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. Trial registration: identifier: NCT01163825. Registered on 14 Jul 2010.

Original languageEnglish
Article number195
JournalAlzheimer's Research and Therapy
Issue number1
Publication statusPublished - 7 Jul 2016

Bibliographical note

Funding Information:
This work was supported by NsGene A/S, grants from the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Power Consortium, King Gustaf V’s and Queen Victoria’s Freemason Foundation, Demensfonden, Olle Engkvist Byggmästare Foundation, Ragnhild and Einar Lundström Memorial Foundation, Gamla Tjänarinnor Foundation, Gun and Bertil Stohnes Foundation, Odd Fellows Memory Foundation, Åke Wiberg Foundation, and Åhlen Foundation. The funding sources had no involvement in any aspect of the study design, data analysis, interpretation or decision to publish this study.

Publisher Copyright:
© 2016 The Author(s).

Other keywords

  • Alzheimer's disease
  • Encapsulated cell biodelivery
  • Nerve growth factor
  • Regenerative medicine


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