The proteasome metabolizes peptide-mediated nonviral gene delivery systems.

Abstract:

:The proteasome is a multisubunit cytosolic protein complex responsible for degrading cytosolic proteins. Several studies have implicated its involvement in the processing of viral particles used for gene delivery, thereby limiting the efficiency of gene transfer. Peptide-based nonviral gene delivery systems are sufficiently similar to viral particles in their size and surface properties and thereby could also be recognized and metabolized by the proteasome. The present study utilized proteasome inhibitors (MG 115 and MG 132) to establish that peptide DNA condensates are metabolized by the proteasome, thereby limiting their gene transfer efficiency. Transfection of HepG2 or cystic fibrosis/T1 (CF/T1) cells with CWK18 DNA condensates in the presence of MG 115 or MG 132 resulted in significantly enhanced gene expression. MG 115 and MG 132 increased luciferase expression 30-fold in a dose-dependent manner in HepG2 and CF/T1. The enhanced gene expression correlated directly with proteasome inhibition, and was not the result of lysosomal enzyme inhibition. The enhanced transfection was specific for peptide DNA condensates, whereas Lipofectamine- and polyethylenimine-mediated gene transfer were significantly blocked. A series of novel gene transfer peptides containing intrinsic GA proteasome inhibitors (CWK18(GA)n, where n=4, 6, 8 and 10) were synthesized and found to inhibit the proteasome. The gene transfer efficiency mediated by these peptides in four different cell lines established that a GA repeat of four is sufficient to block the proteasome and significantly enhance the gene transfer. Together, these results implicate the proteasome as a previously undiscovered route of metabolism of peptide-based nonviral gene delivery systems and provide a rationale for the use of proteasome inhibition to increase gene transfer efficiency.

journal_name

Gene Ther

journal_title

Gene therapy

authors

Kim J,Chen CP,Rice KG

doi

10.1038/sj.gt.3302575

subject

Has Abstract

pub_date

2005-11-01 00:00:00

pages

1581-90

issue

21

eissn

0969-7128

issn

1476-5462

pii

3302575

journal_volume

12

pub_type

杂志文章
  • Development of a nonintegrating Rev-dependent lentiviral vector carrying diphtheria toxin A chain and human TRAF6 to target HIV reservoirs.

    abstract::Persistence of human immunodeficiency virus (HIV) despite highly active antiretroviral therapy (HAART) is a lasting challenge to virus eradication. To develop a strategy complementary to HAART, we constructed a series of Rev-dependent lentiviral vectors carrying diphtheria toxin A chain (DT-A) and its attenuated mutan...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2010.53

    authors: Wang Z,Tang Z,Zheng Y,Yu D,Spear M,Iyer SR,Bishop B,Wu Y

    更新日期:2010-09-01 00:00:00

  • Localized expression of an anti-TNF single-chain antibody prevents development of collagen-induced arthritis.

    abstract::Although systemic administration of neutralizing anti-TNF antibodies has been used successfully in treating rheumatoid arthritis, there is a potential for side effects. We transduced a collagen reactive T-cell hybridoma with tissue-specific homing properties to assess therapeutic effects of local delivery to inflamed ...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301980

    authors: Smith R,Tarner IH,Hollenhorst M,Lin C,Levicnik AU,Fathman CG,Nolan GP

    更新日期:2003-08-01 00:00:00

  • Induction of complement attack on human cells by Gal(alpha1,3)Gal xenoantigen expression as a gene therapy approach to cancer.

    abstract::Galactose(alpha1,3)galactose on the surface of cells of non-primate organs is the major xenoantigen responsible for hyperacute rejection in xenotransplantation. The antigen is synthesised by (alpha1, 3)galactosyl transferase. Humans lack this enzyme and their serum contains high levels of pre-existing natural antibody...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3300934

    authors: Jäger U,Takeuchi Y,Porter C

    更新日期:1999-06-01 00:00:00

  • Stable and monodisperse lipoplex formulations for gene delivery.

    abstract::A stable single vial lipoplex formulation has been developed that can be stored frozen without losing either biological activity or physical stability. This formulation was identified by systematically controlling several formulation variables and without introducing either stabilizers or surfactants. Analytical assay...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3300707

    authors: Zelphati O,Nguyen C,Ferrari M,Felgner J,Tsai Y,Felgner PL

    更新日期:1998-09-01 00:00:00

  • Anti-angiogenic therapy increases intratumoral adenovirus distribution by inducing collagen degradation.

    abstract::Conditionally replicating adenoviruses (CRAd) are a promising class of gene therapy agents that can overcome already known glioblastoma (GBM) resistance mechanisms but have limited distribution upon direct intratumoral (i.t.) injection. Collagen bundles in the extracellular matrix (ECM) have an important role in inhib...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2012.42

    authors: Thaci B,Ulasov IV,Ahmed AU,Ferguson SD,Han Y,Lesniak MS

    更新日期:2013-03-01 00:00:00

  • Chitosan-plasmid nanoparticle formulations for IM and SC delivery of recombinant FGF-2 and PDGF-BB or generation of antibodies.

    abstract::Growth factor therapy is an emerging treatment modality that enhances tissue vascularization, promotes healing and regeneration and can treat a variety of inflammatory diseases. Both recombinant human growth factor proteins and their gene therapy are in human clinical trials to heal chronic wounds. As platelet-derived...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2009.60

    authors: Jean M,Smaoui F,Lavertu M,Méthot S,Bouhdoud L,Buschmann MD,Merzouki A

    更新日期:2009-09-01 00:00:00

  • Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid.

    abstract::For successful cancer gene therapy via intravenous (i.v.) administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), whi...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3302843

    authors: Hatakeyama H,Akita H,Kogure K,Oishi M,Nagasaki Y,Kihira Y,Ueno M,Kobayashi H,Kikuchi H,Harashima H

    更新日期:2007-01-01 00:00:00

  • Genetic design of an optimized packaging cell line for gene vectors transducing human B cells.

    abstract::Viral gene vectors often rely on packaging cell lines, which provide the necessary factors in trans for the formation of virus-like particles. Previously, we reported on a first-generation packaging cell line for gene vectors, which are based on the B-lymphotropic Epstein-Barr virus (EBV), a human gamma-herpesvirus. T...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3302714

    authors: Hettich E,Janz A,Zeidler R,Pich D,Hellebrand E,Weissflog B,Moosmann A,Hammerschmidt W

    更新日期:2006-05-01 00:00:00

  • Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers.

    abstract::Several groups are assessing the use of cationic lipids for respiratory gene therapy. To date no human data are available regarding the safety of intra-pulmonary cationic lipid delivery. In preparation for a trial of pulmonary delivery of the CFTR gene, we have assessed the safety of nebulised lipid GL-67/DOPE/DMPE-PE...

    journal_title:Gene therapy

    pub_type: 临床试验,杂志文章

    doi:10.1038/sj.gt.3300481

    authors: Chadwick SL,Kingston HD,Stern M,Cook RM,O'Connor BJ,Lukasson M,Balfour RP,Rosenberg M,Cheng SH,Smith AE,Meeker DP,Geddes DM,Alton EW

    更新日期:1997-09-01 00:00:00

  • MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats.

    abstract::Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced dru...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2017.22

    authors: Iida T,Yi H,Liu S,Ikegami D,Zheng W,Liu Q,Takahashi K,Kashiwagi Y,Goins WF,Glorioso JC,Hao S

    更新日期:2017-05-01 00:00:00

  • Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV.

    abstract::Choroidal neovascularization (CNV) leads to loss of vision in age-related macular degeneration (AMD), the leading cause of blindness in adult population over 50 years old. In this study, we developed intravenously administered, nanoparticulate, targeted nonviral retinal gene delivery systems for the management of CNV....

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2008.185

    authors: Singh SR,Grossniklaus HE,Kang SJ,Edelhauser HF,Ambati BK,Kompella UB

    更新日期:2009-05-01 00:00:00

  • Tetracycline-inducible transgene expression mediated by a single AAV vector.

    abstract::Regulated gene delivery systems are usually made of two elements: an inducible promoter and a transactivator. In order to optimize gene delivery and regulation, a single viral vector ensuring adequate stoichiometry of the two elements is required. However, efficient regulation is hampered by interferences between the ...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301838

    authors: Chtarto A,Bender HU,Hanemann CO,Kemp T,Lehtonen E,Levivier M,Brotchi J,Velu T,Tenenbaum L

    更新日期:2003-01-01 00:00:00

  • Intrabody-mediated phenotypic knockout of major histocompatibility complex class I expression in human and monkey cell lines and in primary human keratinocytes.

    abstract::Cultured keratinocyte allografts from unrelated donors can be readily grown as sheets in large-scale cell culture and have been used as an immediate skin cover for severely burned patients. Despite the absence of passenger leukocytes and the unlimited amount of material that can be obtained for permanent skin coverage...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301656

    authors: Mhashilkar AM,Doebis C,Seifert M,Busch A,Zani C,Soo Hoo J,Nagy M,Ritter T,Volk HD,Marasco WA

    更新日期:2002-03-01 00:00:00

  • Prolonged organ retention and safety of plasmid DNA administered in polyethylenimine complexes.

    abstract::Polyethylenimine (PEI) has been studied as an efficient nonviral gene transfer vector. Here, we report the biodistribution fates and safety of plasmid DNA intravenously administered in PEI complexes. Using pCMVbeta as a model gene, the biodistribution of plasmid DNA was measured by quantitative polymerase chain reacti...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301516

    authors: Oh YK,Kim JP,Yoon H,Kim JM,Yang JS,Kim CK

    更新日期:2001-10-01 00:00:00

  • Insulin expressed from endogenously active glucose-responsive EGR1 promoter in bone marrow mesenchymal stromal cells as diabetes therapy.

    abstract::Advances in islet transplantation have encouraged efforts to create alternative insulin-secreting cells that overcome limitations associated with current therapies. We have recently demonstrated durable correction of murine and porcine diabetes by syngeneic and autologous implantation, respectively, of primary hepatoc...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2010.12

    authors: Chen NK,Tan SY,Udolph G,Kon OL

    更新日期:2010-05-01 00:00:00

  • Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models.

    abstract::Interferon-alpha (IFN-alpha) or CD80 transduction of tumor cells individually reduces tumorigenicity and enhances antitumor responses. Here, we report that the combination of IFN-alpha and CD80 cancer gene therapy in poorly immunogenic murine tumor models, the colorectal adenocarcinoma cell line MC38, and the methylch...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301034

    authors: Hiroishi K,Tüting T,Tahara H,Lotze MT

    更新日期:1999-12-01 00:00:00

  • Cyclodextrin mediated delivery of NF-κB and SRF siRNA reduces the invasion potential of prostate cancer cells in vitro.

    abstract::Prostate cancer is the most common cancer in men of the western world. To date, no effective treatment exists for metastatic prostate cancer and consequently, there is an urgent need to develop new and improved therapeutics. In recent years, the therapeutic potential of RNA interference (RNAi) has been extensively exp...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2015.50

    authors: Evans JC,McCarthy J,Torres-Fuentes C,Cryan JF,Ogier J,Darcy R,Watson RW,O'Driscoll CM

    更新日期:2015-10-01 00:00:00

  • Impact of deletion of envelope-related genes of recombinant Sendai viruses on immune responses following pulmonary gene transfer of neonatal mice.

    abstract::We demonstrated previously that the additive-type recombinant Sendai virus (rSeV) is highly efficient for use in pulmonary gene transfer; however, rSeV exhibits inflammatory responses. To overcome this problem, we tested newly developed non-transmissible constructs, namely, temperature-sensitive F-deleted vector, rSeV...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3302955

    authors: Tanaka S,Yonemitsu Y,Yoshida K,Okano S,Kondo H,Inoue M,Hasegawa M,Masumoto K,Suita S,Taguchi T,Sueishi K

    更新日期:2007-07-01 00:00:00

  • hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity.

    abstract::We recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression and selectively kills various human cancer cells both in vitro and in xenograft tumors. However, it remains unclear whether the hTERT promoter can be used to induce transgene expression in syn...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301619

    authors: Gu J,Andreeff M,Roth JA,Fang B

    更新日期:2002-01-01 00:00:00

  • Gene therapy progress and prospects: transcription regulatory systems.

    abstract::The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preven...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/sj.gt.3302251

    authors: Toniatti C,Bujard H,Cortese R,Ciliberto G

    更新日期:2004-04-01 00:00:00

  • Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice.

    abstract::Vessel wall inflammation and matrix destruction are critical to abdominal aortic aneurysm (AAA) formation and rupture. We have previously shown that urokinase plasminogen activator (uPA) is highly expressed in experimental AAA and is essential for AAA formation and expansion. In this study, we examined the effects of ...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3303069

    authors: Qian HS,Gu JM,Liu P,Kauser K,Halks-Miller M,Vergona R,Sullivan ME,Dole WP,Deng GG

    更新日期:2008-02-01 00:00:00

  • In vivo gene introduction into keratinocytes using jet injection.

    abstract::Successful keratinocyte gene therapy requires the development of efficient methods of gene transfer to keratinocytes. Jet injection of a solution containing DNA can be used to transfer genes to several tissues in vivo. In this article, we tried to introduce DNA into rat and human keratinocytes using this method. First...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301002

    authors: Sawamura D,Ina S,Itai K,Meng X,Kon A,Tamai K,Hanada K,Hashimoto I

    更新日期:1999-10-01 00:00:00

  • Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease.

    abstract::During the past decade, both in vitro and in vivo studies have provided new insights into the cellular and molecular mechanisms that govern angiogenesis and arteriogenesis. However, therapeutic angiogenesis clinical trials using recombinant protein or gene therapy formulations of single angiogenic growth factors have ...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/sj.gt.3302953

    authors: Vincent KA,Jiang C,Boltje I,Kelly RA

    更新日期:2007-05-01 00:00:00

  • Drug-inducible and simultaneous regulation of endogenous genes by single-chain nuclear receptor-based zinc-finger transcription factor gene switches.

    abstract::Chemically inducible gene switches that regulate expression of endogenous genes have multiple applications for basic gene expression research and gene therapy. Single-chain zinc-finger transcription factors that utilize either estrogen receptor homodimers or retinoid X receptor-alpha/ecdysone receptor heterodimers are...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2008.96

    authors: Magnenat L,Schwimmer LJ,Barbas CF 3rd

    更新日期:2008-09-01 00:00:00

  • Gene therapy progress and prospects--vectorology: design and production of expression cassettes in AAV vectors.

    abstract::Adeno-associated virus (AAV) derived vectors are considered highly eligible vehicles for human gene therapy. Not only do they possess many great potential for clinical applications due to their wide range of tissue targets but also their excellent preclinical safety profile makes them particularly suitable candidates ...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/sj.gt.3302724

    authors: Le Bec C,Douar AM

    更新日期:2006-05-01 00:00:00

  • Encapsulated engineered myoblasts can cure Hurler syndrome: preclinical experiments in the mouse model.

    abstract::Mucopolysaccharidosis type I (MPSI) is an autosomic recessive, lysosomal storage disorder due to the deficit of the enzyme α-L-iduronidase (IDUA). The disease accounts for a general impairment of tissue and organ functions, mainly including heart disease, corneal clouding, organomegaly, skeletal malformations and join...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2011.94

    authors: Piller Puicher E,Tomanin R,Salvalaio M,Friso A,Hortelano G,Marin O,Scarpa M

    更新日期:2012-04-01 00:00:00

  • Towards mutation-independent silencing of genes involved in retinal degeneration by RNA interference.

    abstract::More than one hundred different mutations in the gene encoding rhodopsin are associated with a group of retinal degenerations including retinitis pigmentosa, congenital stationary night blindness and retinitis punctata albescens. Given this large heterogeneity of mutations, it would be ideal to develop mutation-indepe...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3302512

    authors: Cashman SM,Binkley EA,Kumar-Singh R

    更新日期:2005-08-01 00:00:00

  • Expression of interleukin-4 but not of interleukin-10 from a replicative herpes simplex virus type 1 viral vector precludes experimental allergic encephalomyelitis.

    abstract::We have used interleukin (IL)-4 and -10-producing HSV-1 gamma(1)34.5 deletion viruses in gene therapy of a BALB/c model of experimental allergic encephalomyelitis (EAE), a T cell-mediated demyelinating disease of the central nervous system. It is known that in EAE of mice the Th2-type cytokines are down-regulated and ...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3301465

    authors: Broberg E,Setälä N,Röyttä M,Salmi A,Erälinna JP,He B,Roizman B,Hukkanen V

    更新日期:2001-05-01 00:00:00

  • Microwave irradiation enhances gene and oligonucleotide delivery and induces effective exon skipping in myoblasts.

    abstract::Microwave (MW) energy consists of electric and magnetic fields and is able to penetrate deep into biological materials. We investigated the effect of MW (2450 MHz) irradiation on gene delivery in cultured mouse myoblasts and observed enhanced transgene expression. This effect is, however, highly variable and criticall...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/gt.2008.144

    authors: Doran TJ,Lu PJ,Vanier GS,Collins MJ,Wu B,Lu QL

    更新日期:2009-01-01 00:00:00

  • Regeneration of dystrophin-expressing myocytes in the mdx heart by skeletal muscle stem cells.

    abstract::Cell transplantation holds promise as a potential treatment for cardiac dysfunction. Our group has isolated populations of murine skeletal muscle-derived stem cells (MDSCs) that exhibit stem cell-like properties. Here, we investigated the fate of MDSCs after transplantation into the hearts of dystrophin-deficient mdx ...

    journal_title:Gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.gt.3302521

    authors: Payne TR,Oshima H,Sakai T,Ling Y,Gharaibeh B,Cummins J,Huard J

    更新日期:2005-08-01 00:00:00