Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector

Chtarto, Abdelwahed; Yang, Xin; Bockstael, Olivier; Melas, Catherine; Blum, David; Lehtonen, Enni; Abeloos, L.; Jaspar, J-M; Levivier, Marc; Brotchi, Jacques; Velu, Thierry; Tenenbaum, Liliane

doi:10.1016/j.expneurol.2006.11.014

Cited by 51 publications

(49 citation statements)

References 55 publications

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“…Tetracycline-and rapamycin-based inducible systems have previously been used to regulate GDNF expression in vivo. 12,13,[29][30][31][32][33][34] A comparison of our experiments with these studies suggests that the DD system has a lower dynamic range of induction when compared with tetracycline-based systems and a higher range of induction when compared with rapamycin-based systems. Nevertheless, the amount of induced G-F-DD in striatum was able to activate signaling pathways in SNpc and was comparable with therapeutic GDNF levels observed by others, 6 indicating that the DD system could regulate GDNF to levels that are therapeutically relevant.…”

Section: Discussionmentioning

confidence: 95%

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Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson’s Disease

et al. 2013

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Glial cell line-derived neurotrophic factor (GDNF) has great potential to treat Parkinson's disease (PD). However, constitutive expression of GDNF can over time lead to side effects. Therefore, it would be useful to regulate GDNF expression. Recently, a new gene inducible system using destabilizing domains (DD) from E. coli dihydrofolate reductase (DHFR) has been developed and characterized. The advantage of this novel DD is that it is regulated by trimethoprim (TMP), a well-characterized drug that crosses the blood-brain barrier and can therefore be used to regulate gene expression in the brain. We have adapted this system to regulate expression of GDNF. A C-terminal fusion of GDNF and a DD with an additional furin cleavage site was able to be efficiently regulated in vitro, properly processed and was able to bind to canonical GDNF receptors, inducing a signaling cascade response in target cells. In vivo characterization of the protein showed that it could be efficiently induced by TMP and it was only functional when gene expression was turned on. Further characterization in a rodent model of PD showed that the regulated GDNF protected neurons, improved motor behavior of animals and was efficiently regulated in a pathological setting.

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Section: Discussionmentioning

confidence: 95%

“…A previous study by Chtarto and colleagues, 29 where a variant of the tetracyclin-based inducible system was used to regulate GDNF in the 6-OHDA rat model of PD resulted in neuroprotection. However, there were also side effects such as TH downregulation and loss of behavioral improvements.…”

Section: Discussionmentioning

confidence: 97%

Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson’s Disease

et al. 2013

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“…Tissue samples were homogenized in ice cold Tris buffer (containing 2 mM EDTA, 1% NP-40, 2 mM phenylmethylsulphonyl fluoride and 10 lg/ml aprotinin), centrifuged at 12,000 rpm for 20 min and the resultant supernatants were assayed by ELISA kits (Human GDNF CytoSets TM ELISA from Biosource; BDNF DuoSet ELISA Developmental Kit from R & D systems) according to the supplier's protocol. The method of tissue extraction was based on previous reports (Chtarto et al 2007;Kinor et al 2001;Golder et al 2008). Levels of GDNF and BDNF were expressed as picograms per gram of wet brain (pg/g).…”

Section: Gdnf and Bdnf Enzyme-linked Immunosorbent Assaymentioning

confidence: 99%

Deficiency in Endothelin Receptor B Reduces Proliferation of Neuronal Progenitors and Increases Apoptosis in Postnatal Rat Cerebellum

et al. 2008

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Endothelins regulate cellular functions in the mammalian brain through the endothelin receptors A and B (EDNRA and EDNRB). In this study, we investigated the role of EDNRB on cell proliferation in the cerebellum by using the spotting lethal (sl) rat, which carries a naturally occurring deletion in the EDNRB gene. Proliferating cells in the three genotypes, wild-type (+/+), heterozygous (+/sl) and homozygous mutant (sl/sl) rats were labelled by intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU) at postnatal day 2. The density of BrdU-positive cells (per mm(2)) in the external germinal layer of sl/sl rats (Mean +/- SEM, 977 +/- 388) was significantly reduced compared to +/+ (4915 +/- 631) and +/sl (2304 +/- 557) rats. Subsequently, we examined the effects of EDNRB mutation on neural apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelling assay. This showed that the density of apoptotic cells in the cerebella of sl/sl rats (9.3 +/- 0.5/mm(2)) was significantly more increased than +/+ rats (4 +/- 0.7). The expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured with standard ELISA, but were unchanged in all genotypes. These results suggest that ENDRB mediates neural proliferation and have anti-apoptotic effects in the cerebellum of the postnatal rat, and that these effects are independent of changes in the expression of BDNF and GDNF. Our findings will lead to better understanding of the morphological changes in the cerebellum of Hirschsprung's disease patients with congenital EDNRB mutation.

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“…However, most current gene delivery methods to the brain were achieved via direct intracerebral injection of viral vectors such as adeno-associated virus (AAV), because these gene vectors themselves could not cross the BBB through an intravenous injection [1]. This administration method is considered highly invasive, and impractical for repetitive or continuous treatments [2].…”

Section: Introductionmentioning

confidence: 99%

Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model

Huang

Liu

et al. 2010

Journal of the Neurological Sciences

136

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Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector

Cited by 51 publications

References 55 publications

Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson’s Disease

Functional Neuroprotection and Efficient Regulation of GDNF Using Destabilizing Domains in a Rodent Model of Parkinson’s Disease

Deficiency in Endothelin Receptor B Reduces Proliferation of Neuronal Progenitors and Increases Apoptosis in Postnatal Rat Cerebellum

Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model

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