Towards safe, non-viral therapeutic gene expression in humans

Glover, Dominic J.; Lipps, Hans J.; Jans, David A.

doi:10.1038/nrg1577

Cited by 546 publications

(426 citation statements)

References 145 publications

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Section: Discussionmentioning

confidence: 99%

“…Nonviral approaches should provide a safe alternative to viral gene delivery, but are believed to be inefficient, largely owing to the poor nuclear delivery of DNA (Chan and Jans, 2002;Glover et al, 2005). AVs are intended to overcome these problems by incorporating modules that mimic efficient nuclear targeting by viruses (e.g., cell-specific binding/uptake, endosomal escape, and nuclear import; Cohen et al, 2005;Glover et al, 2005;Alvisi et al, 2006; Mastrobattista et al, 2006a,b), while avoiding the pathogenicity associated with viral approaches. We have successfully utilized modular approaches to achieve nuclear drug delivery relevant to chemotherapy (Rosenkranz et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…This is of particular relevance to the development of "artificial viruses" (AVs), in which there is considerable research interest owing to the identification of significant pathogenesis in viral-mediated gene delivery/gene therapy trials (Glover et al, 2005;Mastrobattista et al, 2006b). Nonviral approaches should provide a safe alternative to viral gene delivery, but are believed to be inefficient, largely owing to the poor nuclear delivery of DNA (Chan and Jans, 2002;Glover et al, 2005). AVs are intended to overcome these problems by incorporating modules that mimic efficient nuclear targeting by viruses (e.g., cell-specific binding/uptake, endosomal escape, and nuclear import; Cohen et al, 2005;Glover et al, 2005;Alvisi et al, 2006; Mastrobattista et al, 2006a,b), while avoiding the pathogenicity associated with viral approaches.…”

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confidence: 99%

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Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import

Moseley

Roth

Dejesus

et al. 2007

MBoC

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105

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Nuclear localization sequence (NLS)-dependent nuclear protein import is not conventionally held to require interaction with microtubules (MTs) or components of the MT motor, dynein. Here we report for the first time the role of sequences conferring association with dynein light chains (DLCs) in NLS-dependent nuclear accumulation of the rabies virus P-protein. We find that P-protein nuclear accumulation is significantly enhanced by its dynein light chain association sequence (DLC-AS), dependent on MT integrity and association with DLCs, and that P-protein-DLC complexes can associate with MT cytoskeletal structures. We also find that P-protein DLC-AS, as well as analogous sequences from other proteins, acts as an independent module that can confer enhancement of nuclear accumulation to proteins carrying the P-protein NLS, as well as several heterologous NLSs. Photobleaching experiments in live cells demonstrate that the MT-dependent enhancement of NLS-mediated nuclear accumulation by the P-protein DLC-AS involves an increased rate of nuclear import. This is the first report of DLC-AS enhancement of NLS function, identifying a novel mechanism regulating nuclear transport with relevance to viral and cellular protein biology. Importantly, this data indicates that DLC-ASs represent versatile modules to enhance nuclear delivery with potential therapeutic application. INTRODUCTIONNuclear protein transport is central to normal and aberrant cellular development and physiology, as well as the infectious cycles of intracellular pathogens Hearps and Jans, 2006). The ability to exploit the cellular factors involved in nuclear targeting is of great therapeutic value as it permits the design of vehicles for the efficient delivery of drugs/therapeutic genes to the nuclear compartment (Chan and Jans, 2002; Mastrobattista et al., 2006a,b). All trafficking across the nuclear membrane occurs through the nuclear membrane embedded nuclear pore complex (NPC). The movement of molecules Ͼ45 kDa generally requires active transport, where proteins conventionally interact via a nuclear localization sequence (NLS) with import proteins (importins) which mediate docking to and transit through the NPC . Current understanding of this process focuses largely on these events at the NPC because investigation of nuclear import has conventionally used permeabilized cell systems with associated disruption of cytoplasmic structures. Thus, it is only through recent studies with live cells that it has become clear that nuclear import can involve additional levels of regulation in the cytoplasm involving the microtubule (MT) cytoskeleton (Giannakakou et al., 2000;Lam et al., 2002;Roth et al., 2007), a network composed of ϩ/Ϫ polarized polymers of tubulin with the negative end at the MT organizing center (MTOC) located near the nucleus of nonpolarized cells. MTs are suggested to act as tracks for cargo delivery by molecular motors including the multiprotein complex motor, dynein, which mediates net movement of cargoes toward the MTOC (retrograde movement),...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import

Moseley

Roth

Dejesus

et al. 2007

MBoC

Self Cite

105

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“…However, challenges in developing safe and efficacious gene transfer vectors have limited its clinical application. Synthetic non-viral gene transfer vectors are being developed as alternatives to viral vectors (Glover et al, 2005). Among non-viral gene delivery systems under development are electrostatic complexes derived from cationic liposomes (lipoplexes) (Felgner et al, 1987;Gao and Huang, 1991), cationic polymers (polyplexes) (Boussif et al, 1995;Pack et al, 2005), and lipid-polymer-DNA (LPD) ternary complexes (lipopolyplexes) (Gao and Huang, 1996;Guo et al, 2002;Lee and Huang, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cationic lipid-coated magnetic nanoparticles associated with transferrin for gene delivery

Pan

Guan

Yoo

et al. 2008

International Journal of Pharmaceutics

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Cationic lipid-coated magnetic nanoparticles (MPs) associated with transferrin were evaluated as gene transfer vectors in the presence of a static magnetic field. MPs were prepared by chemical precipitation and were surface-coated with cationic lipids, composed of DDAB/soy PC (60:40 mole/mole). These cationic MPs were then combined with polyethylenimine (PEI) condensed plasmid DNA, followed by transferrin. The resulting magnetic electrostatic complexes retained relatively compact particle size and showed complete DNA condensation. Their transfection activity in the presence of a static magnetic field was evaluated by luciferase and green fluorescent protein (GFP) reporter genes. The magnetic complexes exhibited up to 300-fold higher transfection activity compared to commonly used cationic liposomes or cationic polymer complexes, based on luciferase assay. The enhancement in transfection activity was maximized when the cells were exposed to the vectors for a relatively short period of time (15 min), or were treated in media containing 10% serum. Incorporation of transferrin further improved transfection efficiency of the cationic MPs. However, when cells were incubated for 4 h in serum-free media, magnetic and non-magnetic vectors showed similar transfection efficiencies. In conclusion, transferrin-associated cationic MPs are excellent gene transfer vectors that can mediate very rapid and efficient gene transfer in vitro in the presence of a magnetic field.

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“…Generally, viral (e.g., adenoviruses, lentiviruses and retroviruses) and nonviral vectors (e.g., lipids and polymers) can be used for cellular transfection and/or nucleofection, thus offering durable gene expression within stem cells [93][94][95][96]. Nonviral carriers have a number of advantages over viral vectors, since they exhibit low-risk immunogenicity and insertional mutagenesis, controllable toxicity, and excellent gene-carrying capacity [95]. Many efforts for the improvement of nonviral vectors are focused on cationic polymers that interact with negatively charged DNA or RNAi.…”

Section: A U T H O R P R O O Fmentioning

confidence: 99%

Nanodentistry: Combining Nanostructured Materials and Stem Cells for Dental Tissue Regeneration

2012

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Regenerative dentistry represents an attractive multidisciplinary therapeutic approach that complements traditional restorative/surgery techniques and benefits from recent advances in stem cell biology, molecular biology, genomics and proteomics. Materials science is important in such advances to move regenerative dentistry from the laboratory to the clinic. The design of novel nanostructured materials, such as biomimetic matrices and scaffolds for controlling cell fate and differentiation, and nanoparticles for diagnostics, imaging and targeted treatment, is needed. The combination of nanotechnology, which allows the creation of sophisticated materials with exquisite fine structural detail, and stem cell biology turns out to be increasingly useful in regenerative medicine. The administration to patients of dynamic biological agents comprising stem cells, bioactive scaffolds and/or nanoparticles will certainly increase the regenerative impact of dental pathological tissues. This overview briefly describes some of the actual benefits and future possibilities of nanomaterials in the emerging field of stem cell-based regenerative dentistry.

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Towards safe, non-viral therapeutic gene expression in humans

Cited by 546 publications

References 145 publications

Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import

Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import

Cationic lipid-coated magnetic nanoparticles associated with transferrin for gene delivery

Nanodentistry: Combining Nanostructured Materials and Stem Cells for Dental Tissue Regeneration

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