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

BackgroundTargeted 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.MethodsFour 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.ResultsAll 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.ConclusionsThe 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 registrationClinicalTrials.gov identifier: NCT01163825. Registered on 14 Jul 2010.

NGF steers microglia toward a neuroprotective phenotype

“…Our data point toward these myeloid cells of the brain as the culprit for the severe neurodegeneration observed in anti‐NGF or anti‐TrkA mice (Capsoni et al, ; Capsoni et al, ), a conclusion that might be relevant also for human brain pathologies. Moreover, our results add an important element to the rationale for the therapeutic use of NGF in AD (Cattaneo & Calissano, ; Cattaneo et al, ; Eriksdotter Jönhagen et al, ; Eriksdotter‐Jönhagen et al, ; Eyjolfsdottir et al, ; Tuszynski et al, ). These broadly neuroprotective actions of NGF via microglia enlarge the spectrum of neurons that can be considered NGF targets—way beyond BFCN—thus extending the therapeutic potential of NGF and its derivatives (Capsoni et al, ).…”

Electroencephalography Is a Good Complement to Currently Established Dementia Biomarkers

“…The association between ApoE genotype and qEEG has previously been shown [52]. Combination of qEEG-SPR with cholinergic CSF biomarkers [53,54] might also be of interest.…”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Similarly, the relative contribution of this effect and direct A beta effects on cholinergic receptors toward inciting the cholinergic lesion in AD remains unclear. However, circumventing potential endosome disruptions to provide NGF directly has provided some promising avenues for treatment: an exciting recent trial delivered NGF chronically to the cholinergic basal forebrain by implanting encapsulated NGF producing cells into the basal forebrain of patients with AD (Eyjolfsdottir et al, 2016). This treatment seemed to show promise for stabilizing cholinergic markers and cognitive function (Eyjolfsdottir et al, 2016).…”