Fast Alpha Activity in EEG of Patients With Alzheimer’s Disease Is Paralleled by Changes in Cognition and Cholinergic Markers During Encapsulated Cell Biodelivery of Nerve Growth Factor (original) (raw)
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Alzheimer's research & therapy, 2016
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 i...
Dementia and Geriatric Cognitive Disorders, 2012
No adverse events were related to NGF or the device. All patients completed the study, including removal of implants at 12 months. Positive findings in cognition, EEG and nicotinic receptor binding in 2 of 6 patients were detected. Conclusions: This study demonstrates that surgical implantation and removal of EC-NGF biodelivery to the basal forebrain in AD patients is safe, well tolerated and feasible.
Nerve growth factor in Alzheimer’s disease : biological effects and therapeutic potential
2017
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder against which there is yet no disease modifying or curative treatment. Degeneration of cholinergic basal forebrain (CBF) neurons plays a role in the pathogenesis of AD and these neurons are highly dependent on nerve growth factor (NGF) for growth and survival. NGF has been proposed as a potential therapy for AD, but NGF does not pass the blood-brain barrier and must be delivered locally to the CBF to avoid side-effects. We tested targeted delivery of NGF to the CBF, using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-man trial in AD patients. The primary objective was to examine safety and tolerability and the secondary objective to test for possible effects on cognition and biomarkers. Ten AD patients were implanted stereotactically with NGF-ECB implants targeting the CBF during 12 months (papers II-IV) or 6 months (paper V). Six patients were implanted with firstgeneration implants, which at implan...
Journal of Alzheimer's disease : JAD, 2015
New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at base...
Alzheimer's & Dementia, 2015
Background: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Hypothesis: EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. Result: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-b, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. Conclusion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease
Nature Medicine, 2005
Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.
Behavioural Brain Research, 1993
We report on the clinical outcome of a first case of intracranial infusion of nerve growth factor (NGF) to an Alztmimer patient. The therapeutic attempt is based on animal research showing that NGF stimulates central cholinergic neurons of the type known to be lost during the development of Alzheimer's disease (AD). Furthermore, our own previous clinical experience of infusing NGF to support the survival of intracranially transplanted adrenal chromaffin cells to Parkinsonian patients indicate this approach to be technically possible and safe and clinically of significant potential. Our first case was a 69-year-old woman, with symptoms of dementia since 8 years, lntraventricular infusion of 6,6 mg NGF over three months resulted in a marked transient increase in uptake and binding of [LIC]nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF infusion, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects of the NG F infusion were found. The results of this single case indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.
Journal of Neurosurgery, 2012
Object The authors describe the first clinical trial with encapsulated cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human cell line encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole. Methods Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 im...
Nerve Growth Factor-Based Therapy in Alzheimer’s Disease and Age-Related Macular Degeneration
Frontiers in Neuroscience, 2021
Alzheimer’s disease (AD) is an age-associated neurodegenerative disease which is the most common cause of dementia among the elderly. Imbalance in nerve growth factor (NGF) signaling, metabolism, and/or defect in NGF transport to the basal forebrain cholinergic neurons occurs in patients affected with AD. According to the cholinergic hypothesis, an early and progressive synaptic and neuronal loss in a vulnerable population of basal forebrain involved in memory and learning processes leads to degeneration of cortical and hippocampal projections followed by cognitive impairment with accumulation of misfolded/aggregated Aβ and tau protein. The neuroprotective and regenerative effects of NGF on cholinergic neurons have been largely demonstrated, both in animal models of AD and in living patients. However, the development of this neurotrophin as a disease-modifying therapy in humans is challenged by both delivery limitations (inability to cross the blood–brain barrier (BBB), poor pharmac...
The cholinergic system and treatment response in subtypes of Alzheimer's disease
BACKGROUND: The heterogeneity within Alzheimer's disease (AD) seriously challenges the development of disease modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD, and explored the relevance of subtype stratification in a clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. METHODS: Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy verified AD patients with structural MRI data at baseline and at 6- or 12-months follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. RESULTS: All AD subtypes showed reduced basal forebrain volum...