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.
Highlights
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
Pre-clinical and clinical observations indicate a strong association between cholinergic dysfunction and cognitive impairment in patients with AD [3, 4] that lead to the development of cholinesterase inhibitors (ChEIs)
All patients were treated with ChEI as concomitant medications with a median duration of 17 months before inclusion, and they remained on ChEI treatment throughout the study
Summary
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. Animal studies later indicated that these adverse events were caused by NGF binding to dorsal root ganglion neurons and the hypothalamus, eliciting a pain response and weight loss [13] None of these adverse effects was seen following intra-parenchymal NGF administration in rodents [14]. The safety of intra-parenchymal NGF delivery was further substantiated by the fact that no pain was experienced by patients with Parkinson’s disease who were receiving NGF infusion directly into the striatum [15] or by cognitively impaired primates following transplant of NGF-secreting fibroblasts to the basal forebrain [16]
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