Lethal toxicity caused by expression of shRNA in the mouse striatum: implications for therapeutic design.


:Therapeutic RNA interference (RNAi) has emerged as a promising approach for the treatment of many incurable diseases, including cancer, infectious disease or neurodegenerative disorders. Demonstration of efficacy and safety in animal models is necessary before planning human application. Our group and others have previously shown the potential of this approach for the dominantly inherited neurological disease DYT1 dystonia by achieving potent short-hairpin RNA (shRNA)-mediated silencing of the disease protein, torsinA, in cultured cells. To establish the feasibility of this approach in vivo, we pursued viral delivery of shRNA in two different mouse models. Surprisingly, intrastriatal injections of adeno-associated virus serotype 2/1 (AAV2/1) vectors expressing different shRNAs, whether targeting torsinA expression or mismatched controls, resulted in significant toxicity with progressive weight loss, motor dysfunction and animal demise. Histological analysis showed shRNA-induced neurodegeneration. Toxicity was not observed in animals that received control AAV2/1 encoding no shRNA, and was independent of genotype, occurring in both DYT1 and wild-type animals. Interestingly, the different genetic background of both mouse models influenced toxicity, being earlier and more severe in 129/SvEv than in C57BL/6 mice. In conclusion, our studies demonstrate that expression of shRNA in the mammalian brain can lead to lethal toxicity. Furthermore, the genetic background of rodents modifies their sensitivity to this form of toxicity, a factor that should be taken into consideration in the design of preclinical therapeutic RNAi trials.


Gene Ther


Gene therapy


Martin JN,Wolken N,Brown T,Dauer WT,Ehrlich ME,Gonzalez-Alegre P




Has Abstract


2011-07-01 00:00:00














  • Isolated limb perfusion: a novel delivery system for wild-type p53 and fiber-modified oncolytic adenoviruses to extremity sarcoma.

    abstract::Isolated limb perfusion (ILP) is a limb salvage surgical modality used to deliver chemotherapy and biologic agents to locally advanced and recurrent extremity soft tissue sarcoma (STS), and may be readily tailored for delivery of gene therapy. We set out to test the feasibility of delivering AdFLAGp53 (replication inc...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Hannay J,Davis JJ,Yu D,Liu J,Fang B,Pollock RE,Lev D

    更新日期:2007-04-01 00:00:00

  • MuLV-based vectors pseudotyped with truncated HIV glycoproteins mediate specific gene transfer in CD4+ peripheral blood lymphocytes.

    abstract::Human immunodeficiency virus (HIV) infection ultimately leads to the destruction of the CD4+ lymphocyte subset and the onset of AIDS. In recent years, several gene therapy procedures making use of retroviral vectors that selectively target HIV susceptible cells have been proposed in order to interfere with HIV product...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Lodge R,Subbramanian RA,Forget J,Lemay G,Cohen EA

    更新日期:1998-05-01 00:00:00

  • Establishment of complement-resistant retroviral vector by homologous restriction factor 20 gene.

    abstract::Homologous restriction factor 20 (HRF20, CD59) is one of the complement regulatory factors. In this study, the complement-resistant retroviral vector, which possesses the HRF20 gene as a selection gene, was constructed and examined. The virus-producing cell, transduced with complement-resistant retroviral vector, was ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Hayashi S,Emi N,Okada H,Nagasaka T,Yokoyama I,Takagi H

    更新日期:1998-02-01 00:00:00

  • Using magnetic forces to enhance non-viral gene transfer to airway epithelium in vivo.

    abstract::We have assessed whether magnetic forces (magnetofection) can enhance non-viral gene transfer to the airways. TransMAG(PEI), a superparamagnetic particle was coupled to Lipofectamine 2000 or cationic lipid 67 (GL67)/plasmid DNA (pDNA) liposome complexes. In vitro transfection with these formulations resulted in approx...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Xenariou S,Griesenbach U,Ferrari S,Dean P,Scheule RK,Cheng SH,Geddes DM,Plank C,Alton EW

    更新日期:2006-11-01 00:00:00

  • Adenoviral gene transfer into the normal and injured spinal cord: enhanced transgene stability by combined administration of temperature-sensitive virus and transient immune blockade.

    abstract::This study characterized gene transfer into both normal and injured adult rat dorsal spinal cord using first (E1-/E3-) or second (E1-/E2A125/E3-, temperature-sensitive; ts) generation of replication-defective adenoviral (Ad) vectors. A novel immunosuppressive regimen aimed at blocking CD4/CD45 lymphocytic receptors wa...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Romero MI,Smith GM

    更新日期:1998-12-01 00:00:00

  • PDGF-B gene therapy accelerates bone engineering and oral implant osseointegration.

    abstract::Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of P...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Chang PC,Seol YJ,Cirelli JA,Pellegrini G,Jin Q,Franco LM,Goldstein SA,Chandler LA,Sosnowski B,Giannobile WV

    更新日期:2010-01-01 00:00:00

  • Enhanced transduction of mouse salivary glands with AAV5-based vectors.

    abstract::We previously demonstrated that recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in salivary gland cells in vitro and in vivo. However, it is not known how other rAAV serotypes perform when infused into salivary glands. The capsids of serotypes 4 and 5 are distinct...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Katano H,Kok MR,Cotrim AP,Yamano S,Schmidt M,Afione S,Baum BJ,Chiorini JA

    更新日期:2006-04-01 00:00:00

  • In vivo targeted delivery of CD40 shRNA to mouse intestinal dendritic cells by oral administration of recombinant Sacchromyces cerevisiae.

    abstract::Short hairpin RNA (shRNA)-mediated gene regulation is a commonly used technique for gene manipulation. An efficient and safe delivery system is indispensable when shRNA is delivered into living organisms for gene therapy. Previous studies have proved that DNA and protein can be delivered into dendritic cells (DCs) by ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Zhang L,Zhang T,Wang L,Shao S,Chen Z,Zhang Z

    更新日期:2014-07-01 00:00:00

  • Gene therapy in transplantation in the year 2000: moving towards clinical applications?

    abstract::Transplantation faces several major obstacles that could be overcome by expression of immunomodulatory proteins through application of gene therapy techniques. Gene therapy strategies to prolong graft survival involve gene transfer of immunosuppressive or graft-protecting molecules. Very promising results have been ob...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Guillot C,Le Mauff B,Cuturi MC,Anegon I

    更新日期:2000-01-01 00:00:00

  • Coxsackie adenovirus receptor and alpha nu beta3/alpha nu beta5 integrins in adenovirus gene transfer of rat cochlea.

    abstract::This study was designed to determine whether Coxsackie adenovirus receptor (CAR) and alpha nu beta3/alpha nu beta5 integrin co-receptors are involved in adenovirus gene transfer in the rat cochlea. We find that CAR and integrin co-receptors are expressed in every cell subtype transduced by the adenoviral vector Ad5 De...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Venail F,Wang J,Ruel J,Ballana E,Rebillard G,Eybalin M,Arbones M,Bosch A,Puel JL

    更新日期:2007-01-01 00:00:00

  • Induction of stable RNA interference in mammalian cells.

    abstract::Over the last years, RNA interference (RNAi) has become a widely used technique that permits the knock-down, and hence functional analysis, of individual genes in vertebrate cells. However, the high failure rate of the RNA molecules used in RNAi experiments continues to be a problem. In this paper, I describe a set of...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Cullen BR

    更新日期:2006-03-01 00:00:00

  • Isolation of more potent oncolytic paramyxovirus by bioselection.

    abstract::Newcastle disease virus (NDV) is an oncolytic paramyxovirus with a nonsegmented single-stranded RNA genome. In this report, a recombinant oncolytic NDV was passaged in human tumor xenografts and reisolated and characterized after two rounds of bioselection. Several isolates could be recovered that differed from the pa...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Beier R,Hermiston T,Mumberg D

    更新日期:2013-01-01 00:00:00

  • Augmentation of myocardial transfection using TerplexDNA: a novel gene delivery system.

    abstract::Gene therapy is a potential new strategy for the treatment of cardiovascular disease. The most efficacious method of gene delivery remains a key hurdle to effective gene therapy. We present the application of a novel, nonviral gene delivery system (TerplexDNA) to augment myocardial transfection. The hearts of New Zeal...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Affleck DG,Yu L,Bull DA,Bailey SH,Kim SW

    更新日期:2001-03-01 00:00:00

  • Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus).

    abstract::Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Alba R,Bradshaw AC,Mestre-Francés N,Verdier JM,Henaff D,Baker AH

    更新日期:2012-01-01 00:00:00

  • Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig.

    abstract::Adenoviral vectors deleted of E1 are attractive vehicles for in vivo gene therapy because efficient gene transfer can be achieved. Immune responses to the vector and vector-transduced cells lead to destruction of target cells, inflammation and difficulties with vector readministration. Immune effectors have been ident...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Jooss K,Turka LA,Wilson JM

    更新日期:1998-03-01 00:00:00

  • Multicomponent gene therapy vaccines for lung cancer: effective eradication of established murine tumors in vivo with interleukin-7/herpes simplex thymidine kinase-transduced autologous tumor and ex vivo activated dendritic cells.

    abstract::Multiple antitumor modalities may be necessary to overcome lung tumor-mediated immunosuppression and effectively treat non-small cell lung cancer (NSCLC). To evaluate a multimodality gene therapy approach for control of local tumor growth, a weakly immunogenic murine alveolar cell carcinoma, L1C2, was transduced with ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Sharma S,Miller PW,Stolina M,Zhu L,Huang M,Paul RW,Dubinett SM

    更新日期:1997-12-01 00:00:00

  • Apical barriers to airway epithelial cell gene transfer with amphotropic retroviral vectors.

    abstract::Gene transfer to airway epithelia with amphotropic pseudotyped retroviral vectors is inefficient following apical vector application. To better understand this inefficiency, we localized the expression of Pit2, the amphotropic receptor, in polarized human airway epithelia. Pit2 was expressed on both the apical and bas...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Wang G,Williams G,Xia H,Hickey M,Shao J,Davidson BL,McCray PB

    更新日期:2002-07-01 00:00:00

  • Stable rAAV-mediated transduction of rod and cone photoreceptors in the canine retina.

    abstract::Recombinant adeno-associated virus (rAAV) vectors are attractive candidates for the treatment of inherited and acquired retinal disease. Although rAAV vectors are well characterized in rodent models, a prerequisite to their clinical application in human patients is the thorough evaluation of their efficacy and safety ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Bainbridge JW,Mistry A,Schlichtenbrede FC,Smith A,Broderick C,De Alwis M,Georgiadis A,Taylor PM,Squires M,Sethi C,Charteris D,Thrasher AJ,Sargan D,Ali RR

    更新日期:2003-08-01 00:00:00

  • The relevance of coagulation factor X protection of adenoviruses in human sera.

    abstract::Intravenous delivery of adenoviruses is the optimal route for many gene therapy applications. Once in the blood, coagulation factor X (FX) binds to the adenovirus capsid and protects the virion from natural antibody and classical complement-mediated neutralisation in mice. However, to date, no studies have examined th...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Duffy MR,Doszpoly A,Turner G,Nicklin SA,Baker AH

    更新日期:2016-07-01 00:00:00

  • Utility of Epstein-Barr virus-encoded small RNA promoters for driving the expression of fusion transcripts harboring short hairpin RNAs.

    abstract::To induce RNA interference (RNAi), either small interfering RNAs (siRNAs) are directly introduced into the cell or short hairpin RNAs (shRNAs) are expressed from a DNA vector. At present, shRNAs are commonly synthesized by RNA polymerase III (Pol III) promoters of the H1 and U6 RNAs. In this study, we designed and cha...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Choy EY,Kok KH,Tsao SW,Jin DY

    更新日期:2008-02-01 00:00:00

  • Herpes simplex virus 1 recombinant virions exhibiting the amino terminal fragment of urokinase-type plasminogen activator can enter cells via the cognate receptor.

    abstract::Earlier this laboratory constructed a herpes simplex virus 1 recombinant (R5111) that carries a IL13 ligand inserted into glycoprotein D and can enter cells via the IL13Ralpha2 receptor commonly expressed on the surface of malignant glioma cells. In this report, we describe the properties of two recombinant viruses ca...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Kamiyama H,Zhou G,Roizman B

    更新日期:2006-04-01 00:00:00

  • Enhanced immune costimulatory activity of primary acute myeloid leukaemia blasts after retrovirus-mediated gene transfer of B7.1.

    abstract::Gene modification of malignant cells to express immune stimulators (cytokines and immune costimulators) has provided the basis for a novel form of immunotherapy. Using a MPSV-based retroviral vector with hygromycin resistance gene as a selectable marker, we have studied retrovirus-mediated gene transfer of an immune c...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Hirst WJ,Buggins A,Darling D,Gäken J,Farzaneh F,Mufti GJ

    更新日期:1997-07-01 00:00:00

  • Combination of cabazitaxel and p53 gene therapy abolishes prostate carcinoma tumor growth.

    abstract::For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Tamura RE,Lana MG,Costanzi-Strauss E,Strauss BE

    更新日期:2020-02-01 00:00:00

  • An adenoviral vector-based mucosal vaccine is effective in protection against botulism.

    abstract::A replication-incompetent adenoviral vector encoding the heavy chain C-fragment (H(C)50) of botulinum neurotoxin type C (BoNT/C) was evaluated as a mucosal vaccine against botulism in a mouse model. Single intranasal inoculation of the adenoviral vector elicited a high level of H(C)50-specific IgG, IgG1 and IgG2a in s...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Xu Q,Pichichero ME,Simpson LL,Elias M,Smith LA,Zeng M

    更新日期:2009-03-01 00:00:00

  • Intracellular rate-limiting steps of gene transfer using glycosylated polylysines in cystic fibrosis airway epithelial cells.

    abstract::To identify the intracellular barriers to efficient gene transfer, we studied the intracellular trafficking of biotinylated plasmid DNA complexed with either fluorescein-conjugated lactosylated or mannosylated polylysine by confocal microscopy. Both are known to be taken up by cystic fibrosis airway epithelial cells (...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Grosse S,Tremeau-Bravard A,Aron Y,Briand P,Fajac I

    更新日期:2002-08-01 00:00:00

  • The clinical landscape for SMA in a new therapeutic era.

    abstract::Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular ther...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Talbot K,Tizzano EF

    更新日期:2017-09-01 00:00:00

  • Electroporation-mediated HGF gene transfection protected the kidney against graft injury.

    abstract::The annual rate of kidney graft loss caused by chronic allograft nephropathy (CAN) has not improved over the past decade. Recent reports suggest that acute renal ischemia results in development of CAN. The goal of the present study was to assess the renoprotective potential and safety of hepatocyte growth factor (HGF)...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Isaka Y,Yamada K,Takabatake Y,Mizui M,Miura-Tsujie M,Ichimaru N,Yazawa K,Utsugi R,Okuyama A,Hori M,Imai E,Takahara S

    更新日期:2005-05-01 00:00:00

  • Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma.

    abstract::A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication. Simultaneously, however, it may also enhance antitumor therapy through initiation of proinflammatory, antiviral cytokine responses at the tumor site. The aim of this study was to investigate ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Galivo F,Diaz RM,Wongthida P,Thompson J,Kottke T,Barber G,Melcher A,Vile R

    更新日期:2010-02-01 00:00:00

  • Retroviral delivery of GAD-IgG fusion construct induces tolerance and modulates diabetes: a role for CD4+ regulatory T cells and TGF-beta?

    abstract::Previous studies have demonstrated that antigen-specific tolerance could be induced by lipopolysaccharide (LPS)-stimulated B cells retrovirally transduced with an immunoglobulin-antigen (or epitope-containing peptide) fusion construct. To investigate the mechanism of this gene therapy system, we now adapted this appro...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Song L,Wang J,Wang R,Yu M,Sun Y,Han G,Li Y,Qian J,Scott DW,Kang Y,Soukhareva N,Shen B

    更新日期:2004-10-01 00:00:00

  • Use of herpes simplex virus type 1-based amplicon vector for delivery of small interfering RNA.

    abstract::Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis of mammalian cells. The use of DNA-based plasmid vectors to achieve transient and stable expression of siRNA has been developed to avoid the problems of double-stranded oligonucleotides transfection...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Sabbioni S,Callegari E,Manservigi M,Argnani R,Corallini A,Negrini M,Manservigi R

    更新日期:2007-03-01 00:00:00