Gene Therapy: Optimising DNA Delivery to the Nucleus

Johnson-Saliba, Melanie; Jans, David A.

doi:10.2174/1389450013348245

Cited by 57 publications

(31 citation statements)

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“…Viruses are modified to eliminate their pathogenic properties and adapted to transport the desired therapeutic genetic material. 119 Viral-based vectors have several limitations when administered directly to the host; that is, they may generate innate and specific antiviral immune responses against viral proteins. As a consequence, the half-life of the vector is reduced and some non-desired side effects are usually manifested in the host when viral vectors are systemically applied.…”

Section: 116mentioning

confidence: 99%

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

et al. 2010

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Mesenchymal stem (stromal) cells (MSCs) are a source of circulating progenitors that are able to generate cells of all mesenchymal lineages and to cover cellular demands of injured tissues. The extent of their transdifferentiation plasticity remains controversial. Cells with MSC properties have been obtained from diverse tissues after purification and expansion in vitro. These cellular populations are heterogeneous and under certain conditions show pluripotent-like properties. MSCs present immunosuppressive and anti-inflammatory features and high migratory capacity toward inflamed or remodeling tissues. In this study we review available data regarding factors and signaling axes involved in the chemoattraction and engraftment of MSCs to an injured tissue or to a tissue undergoing active remodeling. Moreover, experimental evidence in support of uses of MSCs as vehicles of therapeutic genes is discussed. Because of its regenerative capacity and its particular immune properties, the liver is a good model to analyze the potential of MSCbased therapies. Finally, the potential application of MSCs and genetically modified MSCs in liver fibrosis and hepatocellular carcinoma (HCC) is proposed in view of available evidence.

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Section: 116mentioning

confidence: 99%

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

et al. 2010

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“…Dex-induced giant pores could help improving the efficiency of therapeutic gene transfection. This process is strongly limited in fully differentiated, nonmitotic cells due to insufficient nuclear translocation of foreign DNA (Verma and Somia, 1997;Anderson, 1998;Mountain, 2000;Johnson-Saliba and Jans, 2001;Chan and Jans, 2002;Lechardeur and Lukacs, 2002;Hebert, 2003;Wiethoff and Middaugh, 2003). DNA transport across the NE is limited by the bulky size of the DNA and the lack of a nuclear localization signal.…”

Section: Potential Clinical Relevancementioning

confidence: 99%

“…Exogenously applied plasmids are usually too large to pass the NPC central channels and thus excluded from the nucleus. Consequently, the efficiency of gene therapy is generally low in fully differentiated quiescent cells (Johnson-Saliba and Jans, 2001;Lechardeur and Lukacs, 2002;Hebert, 2003;Wiethoff and Middaugh, 2003). Transient NPC dilation could help to override the NE barrier.…”

mentioning

confidence: 99%

Nuclear envelope barrier leak induced by dexamethasone

Kastrup¹,

Oberleithner²,

Ludwig³

et al. 2005

Journal Cellular Physiology

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Nuclear pore complexes (NPCs) are multiprotein channels that span the nuclear envelope. They strongly limit the efficiency of gene transfection by restriction of nuclear delivery of exogenously applied therapeutic macromolecules. NPC dilation could significantly increase this efficiency. Recently, it was shown in oocytes of Xenopus laevis that NPCs dilate from about 82 to 110 nm within min after injection of the glucocorticoid analog dexamethasone (dex). In the present paper we analyzed by means of atomic force microscopy the structural details of NPC dilation and correlated them with functional changes in nuclear envelope permeability. 5-11 min after Dex injection NPC dilation was found at its maximum (approximately 140 nm). In addition, a yet unknown configuration, so-called giant pore, up to 300 nm in diameter, was visualized. Giant pore formation was paralleled by an increase in nuclear envelope permeability tested by electrophysiology and confocal fluorescence microscopy. Even large macromolecules lacking any nuclear localization signal (77 kDa FITC-dextran, molecule diameter up to 36 nm) could gain access to the nucleus. We conclude that dex transiently opens unspecific pathways for large macromolecules. Dex treatment could be potentially useful for improving the efficiency of nuclear gene transfection.

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“…The extracellular barriers include transport to the desired cell populations, potential degradation in the plasma. Intracellular barriers include cellular internalization, endosomal escape, vector unpacking, potential degradation in the cytoplasma, and transport into the nucleus [ 24,25 ] (see Fig. 5.2 ).…”

Section: Gene Therapeuticsmentioning

confidence: 99%

Drugs for Long Acting Injections and Implants

Shen

Burgess

2011

Long Acting Injections and Implants

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Long acting injections and implants have been developed for controlled drug delivery to improve therapeutic effects, decrease dosing frequency, and also avoid potential drug toxicity. Many pharmaceutical agents, such as biomacromolecules (e.g. peptides, proteins and gene therapeutics), drugs with poor bioavailability, and drugs for local delivery are good candidates for developing long acting injections and implants. However, not all drugs are suitable for these formulations (for example, drugs with high dose or narrow therapeutic index). IntroductionDrug formulations should deliver the API (active pharmaceutical agent) to the site of action at the correct therapeutic concentration for as long as the treatment is desired. The therapeutic and the physicochemical properties of a drug determine the preferred route of administration (oral or parenteral) as well as the most appropriate delivery systems.Due to convenience and patient acceptability, oral drug delivery is the most attractive and preferred route for administering medicines. However, some drugs cannot be tolerated via the oral route due to the acid environment and the variety of proteolytic enzymes (proteases) in the gastrointestinal tract (GIT). These conditions tend to degrade or metabolize drugs such as proteins and peptides, resulting in low bioavailability [ 1 ] . Moreover, patients who are unable to tolerate oral ingestion (e.g. patients with aspiration problems or GI disorders) require nonoral administration (e.g. parenteral administration) to receive medications and nutrition. Parenteral administration (e.g. intravenous, intramuscular, and subcutaneous) is also useful

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Gene Therapy: Optimising DNA Delivery to the Nucleus

Cited by 57 publications

References 0 publications

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

Nuclear envelope barrier leak induced by dexamethasone

Drugs for Long Acting Injections and Implants

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