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














  • Interleukin-10 expression induced by adeno-associated virus vector suppresses proteinuria in Zucker obese rats.

    abstract::Varying degrees of metabolic abnormalities mediated by chronic inflammation are implicated in the chronic glomerular injuries associated with obesity. Interleukin (IL)-10, a pleiotropic cytokine, exerts anti-inflammatory effects in numerous biological settings. In the present study, we explored the biological benefits...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Ogura M,Urabe M,Akimoto T,Onishi A,Ito C,Ito T,Tsukahara T,Mizukami H,Kume A,Muto S,Kusano E,Ozawa K

    更新日期:2012-05-01 00:00:00

  • Proliferating endothelial cell-specific expression of IGF-I receptor ribozyme inhibits retinal neovascularization.

    abstract::Insulin-like growth factor-I (IGF-I) and its receptor (IGF-IR) are essential for normal ocular development and are expressed in numerous ocular cell types including lens epithelial cells, retinal pigment epithelial cells, Müller cells and endothelial cells. Endothelial cell proliferation is a common feature of prolife...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Shaw LC,Pan H,Afzal A,Calzi SL,Spoerri PE,Sullivan SM,Grant MB

    更新日期:2006-05-01 00:00:00

  • Particle-mediated gene transfer into murine livers using a newly developed gene gun.

    abstract::Although particle-mediated gene transfer using gene gun technology has been applied for gene transfer into epidermis, applications of this technology to visceral tissues have not been well investigated. Although all helium gas-driven gene gun instruments have used macrocarriers to discharge DNA-coated microprojectiles...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Kuriyama S,Mitoro A,Tsujinoue H,Nakatani T,Yoshiji H,Tsujimoto T,Yamazaki M,Fukui H

    更新日期:2000-07-01 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

  • Potential therapeutic applications of recombinant, invasive E. coli.

    abstract::An invasive Escherichia coli expressing the inv gene from Yersinia pseudotuberculosis was used as a vector for protein delivery to mammalian epithelial cells. Upon incubation with beta1-integrin-expressing mammalian cells, the bacteria are internalized, allowing bacteria-encoded proteins to function from within the ma...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Critchley RJ,Jezzard S,Radford KJ,Goussard S,Lemoine NR,Grillot-Courvalin C,Vassaux G

    更新日期:2004-08-01 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

  • Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss.

    abstract::Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this st...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Yu H,Li Q,Herbert B,Zinna R,Martin K,Junior CR,Kirkwood KL

    更新日期:2011-04-01 00:00:00

  • Expression of the human glucocerebrosidase and arylsulfatase A genes in murine and patient primary fibroblasts transduced by an adeno-associated virus vector.

    abstract::We have constructed two recombinant adeno-associated virus (AAV) vectors (pJJ-3GC and pJJ-3ASA) which contained either the human glucocerebrosidase (GC) or arylsulfatase A (ASA) cDNA under the control of an SV40 promoter. These plasmids were co-transfected to 293 cells with a helper plasmid containing trans-acting AAV...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Wei JF,Wei FS,Samulski RJ,Barranger JA

    更新日期:1994-07-01 00:00:00

  • Expression of beta-galactosidase in mouse brain: utilization of a novel nonreplicative Sindbis virus vector as a neuronal gene delivery system.

    abstract::Sindbis virus expression has been used for in vitro investigations of antigen processing, presentation and epitope mapping. The recent development of a replication-deficient recombinant Sindbis virus expression vector has made in vivo expression possible with minimal pathogenic risk. Advantages of Sindbis virus over o...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Altman-Hamamdzic S,Groseclose C,Ma JX,Hamamdzic D,Vrindavanam NS,Middaugh LD,Parratto NP,Sallee FR

    更新日期:1997-08-01 00:00:00

  • Tackling breast cancer chemoresistance with nano-formulated siRNA.

    abstract::Breast cancer is the leading cancer diagnosed in women and the second leading cause of cancer-related deaths in women. Current limitations to standard chemotherapy in the clinic are extensively researched, including problems arising from repeated treatments with the same drugs. The phenomenon that cancer cells become ...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Jones SK,Merkel OM

    更新日期:2016-12-01 00:00:00

  • DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes.

    abstract::Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for tre...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Riedel MJ,Gaddy DF,Asadi A,Robbins PD,Kieffer TJ

    更新日期:2010-02-01 00:00:00

  • 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


    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

  • Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis.

    abstract::Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Jacobi J,Tam BY,Sundram U,von Degenfeld G,Blau HM,Kuo CJ,Cooke JP

    更新日期:2004-02-01 00:00:00

  • Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo.

    abstract::Bone marrow stromal cells (MSCs) are pluripotent cells capable of differentiation into several tissue types. This present study was performed to determine their functional neoangiogenic potential in vivo. Whole bone marrow was harvested from C57Bl/6 mice, and the adherent cellular fraction was culture expanded for 14 ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Al-Khaldi A,Eliopoulos N,Martineau D,Lejeune L,Lachapelle K,Galipeau J

    更新日期:2003-04-01 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

  • Gene therapy progress and prospects: stem cell plasticity.

    abstract::With the identification of stem cell plasticity several years ago, multiple reports raised hopes that tissue repair by stem cell transplantation could be within reach in the near future. Krause et al reported that a single purified hematopoietic stem cell not only repopulated the bone marrow of a host animal, but also...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Kashofer K,Bonnet D

    更新日期:2005-08-01 00:00:00

  • Tf-lipoplex-mediated NGF gene transfer to the CNS: neuronal protection and recovery in an excitotoxic model of brain injury.

    abstract::The development of efficient systems for in vivo gene transfer to the central nervous system (CNS) may provide a useful therapeutic strategy for the alleviation of several neurological disorders. In this study, we evaluated the feasibility of nonviral gene therapy to the CNS mediated by cationic liposomes. We present ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: da Cruz MT,Cardoso AL,de Almeida LP,Simões S,de Lima MC

    更新日期:2005-08-01 00:00:00

  • Functional correction of T cells derived from patients with the Wiskott-Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein.

    abstract::T-cell dysfunction is thought to be central to the immunodeficiency state seen in patients with the Wiskott-Aldrich syndrome (WAS). Aspects of the WAS phenotype have been corrected in other cell types on introduction of the normal WAS protein (WASP), but the potential for correction of the T-cell defects has not been ...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Strom TS,Gabbard W,Kelly PF,Cunningham JM,Nienhuis AW

    更新日期:2003-05-01 00:00:00

  • Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product.

    abstract::Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscular disorder caused by a defect in the DMD gene. AAV vector-mediated micro-dystrophin cDNA transfer is an attractive approach to treatment of DMD. To establish effective gene transfer into skeletal muscle, we examined the transduction efficiency of an AAV v...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Yuasa K,Sakamoto M,Miyagoe-Suzuki Y,Tanouchi A,Yamamoto H,Li J,Chamberlain JS,Xiao X,Takeda S

    更新日期:2002-12-01 00:00:00

  • Evaluation of recombinant alphaviruses as vectors in gene therapy.

    abstract::Alphavirus vectors based on Sindbis virus and Semliki Forest virus (SFV) were characterized as potential gene transfer vectors. Initial studies were performed using vectors engineered to transfer either lacZ or green fluorescent protein (GFP). High levels of gene transfer were achieved in human primary fibroblasts, BH...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Wahlfors JJ,Zullo SA,Loimas S,Nelson DM,Morgan RA

    更新日期:2000-03-01 00:00:00

  • Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo.

    abstract::Recombinant adenoviruses (Ad) are attractive vectors for gene transfer in vitro and in vivo. However, the widely used E1-deleted vectors as well as newer generation vectors contain viral sequences, including transcriptional elements for viral gene expression. These viral regulatory elements can interfere with heterolo...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Steinwaerder DS,Lieber A

    更新日期:2000-04-01 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


    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

  • Gene therapy for pancreatitis pain.

    abstract::Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replica...

    journal_title:Gene therapy

    pub_type: 杂志文章,评审


    authors: Westlund KN

    更新日期:2009-04-01 00:00:00

  • Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy.

    abstract::Solid tumors meet their demands for nascent blood vessels and increased glycolysis, to combat hypoxia, by activating multiple genes involved in angiogenesis and glucose metabolism. Hypoxia inducible factor-1 (HIF-1) is a constitutively expressed basic helix-loop-helix transcription factor, formed by the assembly of HI...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Sun X,Kanwar JR,Leung E,Lehnert K,Wang D,Krissansen GW

    更新日期:2001-04-01 00:00:00

  • B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity.

    abstract::Chimeric antigen receptor (CAR) T-cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B-cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs that target solid tumors and have t...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Wu MR,Zhang T,DeMars LR,Sentman CL

    更新日期:2015-08-01 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

  • High-titer recombinant adeno-associated virus production utilizing a recombinant herpes simplex virus type I vector expressing AAV-2 Rep and Cap.

    abstract::Recombinant adeno-associated virus type 2 (rAAV) vectors have recently been used to achieve long-term, high level transduction in vivo. Further development of rAAV vectors for clinical use requires significant technological improvements in large-scale vector production. In order to facilitate the production of rAAV ve...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Conway JE,Rhys CM,Zolotukhin I,Zolotukhin S,Muzyczka N,Hayward GS,Byrne BJ

    更新日期:1999-06-01 00:00:00

  • Fibroblasts modulate cardiomyocyte excitability: implications for cardiac gene therapy.

    abstract::In an earlier study exploring the potential of gene transfer to repair myocardial conduction defects, we observed that myotubes, generated by forced expression of MyoD, exhibit reduced excitability when also modified to express connexin43 (Cx43). We hypothesized that this effect was caused by gap junction-mediated cou...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Kizana E,Ginn SL,Smyth CM,Boyd A,Thomas SP,Allen DG,Ross DL,Alexander IE

    更新日期:2006-11-01 00:00:00

  • Low-speed centrifugation of retroviral vectors absorbed to a particulate substrate: a highly effective means of enhancing retroviral titre.

    abstract::For many gene therapy applications the effective titre of retroviral vectors is a limiting factor both in vitro and in vivo. Purification and concentration of retrovirus from packaging cell supernatant can overcome this problem. To this end we have investigated a novel procedure which involves complexing retrovirus to...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: Darling D,Hughes C,Galea-Lauri J,Gäken J,Trayner ID,Kuiper M,Farzaneh F

    更新日期:2000-06-01 00:00:00

  • Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression.

    abstract::Replicating viruses for cancer gene therapy have beneficial antitumor effects, however, in the setting of an enzyme/prodrug system, the interactions between these viruses and the activated agents are complex. A replicating vaccinia virus expressing the cytosine deaminase gene (VVCD), which converts the prodrug 5-FC in...

    journal_title:Gene therapy

    pub_type: 杂志文章


    authors: McCart JA,Puhlmann M,Lee J,Hu Y,Libutti SK,Alexander HR,Bartlett DL

    更新日期:2000-07-01 00:00:00