Novel disease-specific promoters for use in gene therapy for Parkinson's disease

Wettergren, Erika Elgstrand; Gussing, Fredrik; Quintino, Luís; Lundberg, Cecilia

doi:10.1016/j.neulet.2012.09.059

Cited by 15 publications

(16 citation statements)

References 19 publications

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“…The plasmid pHR-CMV-GDNF, 42 enabling constitutive GDNF expression, and the plasmid expressing GDNF-F-DD alone (pHG-CMV-GDNF-F-DD) have been described in detail previously. 10 Gateway technology (Life Technologies Europe, Stockholm, Sweden) was used to clone most of the LVs.…”

Section: Methodsmentioning

confidence: 99%

“…LV production 42 , 44 and titration 10 have been described in detail elsewhere. The LV used for the experiments had the functional titers of 1 × 10 9 transducing units per milliliter.…”

Section: Methodsmentioning

confidence: 99%

“…The aesthetic solutions and general surgical procedures have been described elsewhere. 42 Bilateral injections with triple-injection sites were performed in the following coordinates from bregma. Coordinates for the right hemisphere were: (1) anterioposterior (AP), +1.4 mm; mediolateral (ML), −2.6 mm; and dorsoventral (DV), −5/−4 mm; (2) AP, +0.4 mm; ML, −3.8 mm; and DV, −5/−4 mm; and (3) AP, −0.8 mm; ML, −4.4 mm; and DV −5/−4 mm.…”

Section: Methodsmentioning

confidence: 99%

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Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

Quintino

Namislo

Davidsson

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Regulation of therapeutic transgene expression can increase the safety of gene therapy interventions, especially when targeting critical organs such as the brain. Although several gene expression systems have been described, none of the current systems has the required safety profile for clinical applications. Our group has previously adapted a system for novel gene regulation based on the destabilizing domain degron technology to successfully regulate glial cell-line derived neurotrophic factor in the brain (GDNF-F-DD). In the present study, we used GDNF-F-DD as a proof-of-principle molecule to fully characterize DD regulation in the brain. Our results indicate that DD could be regulated in a dose-dependent manner. In addition, GDNF-F-DD could also be induced in vivo repeatedly, without loss of activity or efficacy in vivo. Finally, DD regulation was able to be sustained for 24 weeks without loss of expression or any overt toxicity. The present study shows that DD has great potential to regulate gene expression in the brain.

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Section: Methodsmentioning

confidence: 99%

“…LV production 42 , 44 and titration 10 have been described in detail elsewhere. The LV used for the experiments had the functional titers of 1 × 10 9 transducing units per milliliter.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

Quintino

Namislo

Davidsson

et al. 2018

Molecular Therapy - Methods & Clinical Development

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“…All anesthetic solutions and general procedures have been described in more detail previously. 38 For the animal experiment testing secretion and function of G-F-DD in unlesioned animals, viral suspensions were delivered to two sets of coordinates: (i) Anteroposterior from bregma (AP) +1. Behavioral tests.…”

Section: Methodsmentioning

confidence: 99%

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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“…The use of such disease-specific promoters has been modestly studied for the expression of marker genes [31], [32]. LOX1 encodes for a scavenger receptor which binds oxidized low density lipoprotein (Ox-LDL) and is expressed by activated endothelial cells, smooth muscle cells, and macrophages, the major cell types believed involved in atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Efficacy of the Disease-Specific LOX1- and Constitutive Cytomegalovirus-Promoters in Expressing Interleukin 10 through Adeno-Associated Virus 2/8 Delivery in Atherosclerotic Mice

et al. 2014

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The development of gene therapy vectors for treating diseases of the cardiovascular system continues at a steady pace. Moreover, in the field of gene therapy the utility of “disease-specific promoters” has strong appeal. Many therapeutic genes, including transforming growth factor beta 1 or interleukin 10, are associated to adverse effects. The use of a disease-specific promoter might minimize toxicity. The lectin-like oxidized low density lipoprotein receptor 1 is a marker of cardiovascular disease and a potential therapeutic target. The lectin-like oxidized low density lipoprotein receptor 1 is known to be up-regulated early during disease onset in a number of cell types at the sites where the disease will be clinically evident. In this study an adeno-associated virus-2 DNA vector (AAV2) using the AAV8 capsid, and containing the full length The lectin-like oxidized low density lipoprotein receptor 1 promoter, was generated and assayed for its ability to express human interleukin 10 in low density lipoprotein receptor knockout mice on high cholesterol diet. The cytomegalovirus early promoter was used for comparison in a similarly structured vector. The two promoters were found to have equal efficacy in reducing atherogenesis as measured by aortic systolic blood velocity, aortic cross sectional area, and aortic wall thickness. This is the first head-to-head comparison of a constitutive with a disease-specific promoter in a therapeutic context. These data strongly suggest that the use of a disease-specific promoter is appropriate for therapeutic gene delivery.

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Novel disease-specific promoters for use in gene therapy for Parkinson's disease

Cited by 15 publications

References 19 publications

Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

Destabilizing Domains Enable Long-Term and Inert Regulation of GDNF Expression in the Brain

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

Comparison of Efficacy of the Disease-Specific LOX1- and Constitutive Cytomegalovirus-Promoters in Expressing Interleukin 10 through Adeno-Associated Virus 2/8 Delivery in Atherosclerotic Mice

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