Journal Article

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

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

2016

Overview

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 ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Acetylcholinesterase - metabolism / Aged / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - diagnostic imaging / Alzheimer Disease - drug therapy / Alzheimer's disease / Amyloid beta-Peptides - cerebrospinal fluid / Analysis / Basal Forebrain - diagnostic imaging / Basal Forebrain - drug effects / Biomedical and Life Sciences / Biomedicine / brain / Capsules / Care and treatment / Cell Line / cerebrospinal-fluid / Choline O-Acetyltransferase - cerebrospinal fluid / Clinical Medicine / Cognition Disorders - etiology / Cohort Studies / csf / Dose-Response Relationship, Drug / Drug Delivery Systems / Encapsulated cell biodelivery / Female / gene / Gene expression / Geriatric Psychiatry / Geriatrics/Gerontology / Health aspects / Humans / Intermediate filament proteins / Klinisk medicin / Male / Middle Aged / Nerve growth factor / Nerve Growth Factor - administration & dosage / Nerve Tissue Proteins - cerebrospinal fluid / neurodegenerative diseases / Neurology / Neurosciences / ngf / Peptide Fragments - cerebrospinal fluid / protein / Regenerative medicine / sleeping-beauty / tau Proteins - cerebrospinal fluid / technology / therapy / Treatment Outcome