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Regulated lentiviral NGF gene transfer controls rescue of medial septal cholinergic neurons

Department of Neurosciences-0626, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Molecular Therapy (Impact Factor: 6.43). 06/2005; 11(6):916-25. DOI: 10.1016/j.ymthe.2005.01.007
Source: PubMed

ABSTRACT Nerve growth factor (NGF) has been shown to promote survival and function of cholinergic neurons in the basal forebrain in various models of neuronal degeneration in rodents and primates. We examined whether a regulatable in vivo expression system can control the survival of cholinergic neurons after injury, using a tetracycline-regulated promoter ("tet-off" system) to modulate lentiviral NGF gene delivery. Two weeks after lesions to cholinergic neurons, significant cell rescue (65+/-8% neuron survival; P<0.005 compared to controls) was observed when NGF expression was activated. Treatment with the tetracycline analog doxycycline to turn gene expression "off" resulted in a significant loss of cholinergic neurons (only 37+/-5% neurons remained, an amount that did not differ from untreated, lesioned controls). Animals treated with a constitutively active and robust nonregulated NGF expression system showed the same degree of neuronal rescue (73+/-8%) as animals treated with activated tet-regulated vectors. ELISA measurements confirmed that oral treatment of animals with doxycycline reduced NGF protein levels to levels in untreated control subjects. These data demonstrate for the first time that NGF delivery by lentiviral gene transfer using tetracycline-regulated promoters can completely regulate neuronal rescue and protein production in the brain.

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    • "It has been shown that neurotrophins, especially NGF and BDNF, can have a neuroprotective effect in AD-like conditions (Wang et al., 2002; Skaper, 2008; Bruno et al., 2009). NGF injection prevents degeneration of cholinergic neurons after fornix lesion or administration of toxins (Williams et al., 1986; Koliatsos et al., 1990; Charles et al., 1996; Blesch et al., 2005; Skaper, 2008). Successful experiments on NGF-producing fibroblasts transplantation into the affected brain structures were reported (Rosenberg et al., 1988; Chen and Gage, 1995; Tuszynski et al., 1996). "
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    ABSTRACT: We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50nM beta-amyloid (25-35) 1h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment. Copyright © 2015. Published by Elsevier B.V.
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    • "Moreover, Dox is orally bio‐ available, has a half-life of 14-22 hrs and has an excellent tissue penetration. Therefore numerous groups have used both the Tet-on and Tet-off system within LV-based gene re‐ porter and therapeutic applications (Blomer, Naldini et al. 1997; Bahi, Boyer et al. 2004; Blesch, Conner et al. 2005; Liu, Wang et al. 2008; Hioki, Kuramoto et al. 2009; Adriani, Boyer et al. 2010). This is exemplified by a study of Seo et al. who developed an oncolytic LVmediated Tet-on inducible system based on co-transduction of two LVs to drive the expres‐ sion of a pro-apoptotic gene by the promoter of matrix-metalloproteinase-2 (MMP-2), which is highly expressed in several cancer cell lines. "
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    • "In addition, administration of a lentiviral construct expressing BDNF into rodent and primate models of AD showed improved cell signaling and a restoration of learning and memory, while reversing synaptic loss [65]. Lentiviral NGF gene delivery in rats has been just as beneficial in preventing cholinergic neuron loss upon fimbria-fornix lesion injury [66]. Currently ongoing and future clinical trials in human subjects using both BDNF and NGF viral delivery should inform about their safety and efficacy, and their potential benefits. "
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