Nerve growth factor in Alzheimer’s disease : biological effects and therapeutic potential

Abstract: 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 implant retrieval showed a low NGF release. Following improvements of implants and cell survival, implantations of second-generation NGF-ECB implants were performed in four AD patients. The patients were monitored with regard to safety, tolerability and secondary outcome measures. In paper II, we investigated CSF activity of the cholinergic marker choline acetyltransferase (ChAT) and found that in half of the patients, ChAT activity was significantly increased at 12 months of NGF delivery, compared to an age matched AD reference group. ChAT activity also correlated significantly with cognition, nicotinic binding and brain glucose utilization as well as brain atrophy and CSF biomarkers. In paper III, effects of the NGF delivery on EEG activity were investigated. A significant correlative pattern between alpha power and a) changes in cognition and b) CSF ChAT activity during the 12 month trial was found, indicating that the more stable cognition or increase in cholinergic activity, the more normalized the EEG activity. In paper IV, we investigated changes in brain atrophy on magnetic resonance imaging (MRI) over 12 months of NGF delivery and found that half of the patients showed less brain shrinkage, compared to an age matched AD reference group, and a better progression in clinical variables and CSF biomarkers. In paper V, in four AD patients implanted with second generation NGF-ECB implants for six months, we demonstrated safety and tolerability and at retrieval at six months, the implants exhibited high NGF release and good cell viability. All four patients could complete the study and no adverse advents were deemed related to the implants or NGF delivery. Also in these four patients, a significant pattern of correlations between ChAT activity and cognition and nicotinic binding was shown. In paper I, we investigated levels of pro and mature neurotrophins in subjects with AD, mild cognitive impairment (MCI) and subjective cognitive impairment (SCI). Our results showed the presence of both pro and mature forms of NGF in human CSF. Increased proNGF levels in the MCI group were found compared to AD, and a pathological biomarker profile in CSF from MCI subjects was associated with higher proNGF levels. In conclusion, our studies on NGF delivery in ten AD patients are the first cell therapy studies in the world demonstrating that implantation of encapsulated cells releasing NGF into the CBF in AD patients is safe and well tolerated. Stable cognition correlated with markers of increased cholinergic activity, indicative of a stimulation of the cholinergic system and a possible slowing of the neurodegenerative process.

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