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296:(Figure 2b). Designed to express two or more shRNAs, they can simultaneously target multiple sequences for degradation hence particularly a useful strategy for targeting viruses. Natural sequence variations can render a single shRNA-target site unrecognizable, preventing RNA degradation. Multi-cassette constructs that target multiple sites within the same viral RNA circumvent this issue.
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248:) therapeutics that turn over within a cell and consequently only silence genes transiently, DNA constructs are continually transcribed, replenishing the cellular ‘dose’ of short-hairpin RNA (shRNA), thereby enabling long-term silencing of targeted genes. The ddRNAi mechanism, therefore, offers the potential for ongoing clinical benefit with reduced medical intervention.
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sequences of 20–30 nucleotides. Flexibility in construct design is possible; for example, the positions of sense and antisense sequences can be reversed, and other modifications and additions can alter intracellular shRNA processing. Moreover, a variety of promoter loop and terminator sequences can be used.
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Senzer, N.; Barve, M.; Kuhn, J.; Melnyk, A.; Beitsch, P.; Lazar, M.; Lifshitz, S.; Magee, M.; Oh, J.; Mill, S. W.; Bedell, C.; Higgs, C.; Kumar, P.; Yu, Y.; Norvell, F.; Phalon, C.; Taquet, N.; Rao, D. D.; Wang, Z.; Jay, C. M.; Pappen, B. O.; Wallraven, G.; Brunicardi, F. C.; Shanahan, D. M.; Maples,
386:
Two conserved PKCγ sequences across all key model species and humans have been identified, and both single and double DNA cassettes are designed. In vitro, the expression of PKCγ was silenced by 80%. When similar DDRNAI constructs were delivered intrathecally using a lentiviral vector, pain relief in
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Kleinman, M. E.; Yamada, K.; Takeda, A.; Chandrasekaran, V.; Nozaki, M.; Baffi, J. Z.; Albuquerque, R. J. C.; Yamasaki, S.; Itaya, M.; Pan, Y.; Appukuttan, B.; Gibbs, D.; Yang, Z.; Karikó, K.; Ambati, B. K.; Wilgus, T. A.; Dipietro, L. A.; Sakurai, E.; Zhang, K.; Smith, J. R.; Taylor, E. W.; Ambati,
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infection has not been associated with the induction of cancers in humans despite widespread prevalence across the general population. Moreover, extensive clinical use of AAV vectors has provided no evidence of carcinogenicity. While lentiviral vectors do integrate into the genome they do not appear
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vectors developed for the purpose. Delivery is a major challenge for RNAi-based therapeutics with new modifications and reagents continually being developed to optimize target cell delivery. Two broad strategies to facilitate the delivery of DNA constructs to the desired cells are available: these
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sequence driving the expression of sense and antisense sequences separated by a loop sequence, followed by a transcriptional terminator. The antisense sequence processed from the shRNA can bind to the target RNA and specify its degradation. shRNA constructs typically encode sense and antisense
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for replication. Biomics
Biotechnologies has evaluated around 5000 siRNA sequences of this gene for effective knockdown; five sequences were chosen for further investigation and shown to have potent silencing activity when converted into shRNA expression cassettes. A multi-cassette construct,
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siRNAs have been shown to activate immune responses through interaction with Toll-like receptors leading to interferon responses. These receptors reside on the cell's surface and so DDRNAI constructs – delivered directly into intracellular space – are not expected to induce this response.
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Trollet, C.; Anvar, S. Y.; Venema, A.; Hargreaves, I. P.; Foster, K.; Vignaud, A.; Ferry, A.; Negroni, E.; Hourde, C.; Baraibar, M. A.; "t" hoen, P. A. C.; Davies, J. E.; Rubinsztein, D. C.; Heales, S. J.; Mouly, V.; Van Der Maarel, S. M.; Butler-Browne, G.; Raz, V.; Dickson, G. (2010).
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Suhy, D. A.; Kao, S. C.; Mao, T.; Whiteley, L.; Denise, H.; Souberbielle, B.; Burdick, A. D.; Hayes, K.; Wright, J. F.; Lavender, H.; Roelvink, P.; Kolykhalov, A.; Brady, K.; Moschos, S. A.; Hauck, B.; Zelenaia, O.; Zhou, S.; Scribner, C.; High, K. A.; Renison, S. H.; Corbau, R. (2012).
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An immunological response to an adenoviral vector resulted in the death of a patient in an early human trial. Careful monitoring of potential toxicities in preclinical testing and analyses of pre-existing antibodies to gene therapy vectors in patients minimizes such risks.
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Ringpis, G. E. E.; Shimizu, S.; Arokium, H.; Camba-Colón, J.; Carroll, M. V.; Cortado, R.; Xie, Y.; Kim, P. Y.; Sahakyan, A.; Lowe, E. L.; Narukawa, M.; Kandarian, F. N.; Burke, B. P.; Symonds, G. P.; An, D. S.; Chen, I. S.; Kamata, M. (2012). Speck, Roberto F (ed.).
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Rice, R. R.; Muirhead, A. N.; Harrison, B. T.; Kassianos, A. J.; Sedlak, P. L.; Maugeri, N. J.; Goss, P. J.; Davey, J. R.; James, D. E.; Graham, M. W. (2005). "Simple, Robust
Strategies for Generating DNA-Directed RNA Interference Constructs".
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Tributarna is a triple DNA cassette expressing three shRNA molecules each of which separately targets beta III tubulin and strongly inhibits its expression. Studies in an orthotopic-mouse model, where the construct is delivered by a modified
205:, that bring about the silencing of a target gene or genes once processed. Any RNA, including endogenous messenger RNA (mRNAs) or viral RNAs, can be silenced by designing constructs to express double-stranded RNA complementary to the desired
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Digiusto, D. L.; Krishnan, A.; Li, L.; Li, H.; Li, S.; Rao, A.; Mi, S.; Yam, P.; Stinson, S.; Kalos, M.; Alvarnas, J.; Lacey, S. F.; Yee, J. -K.; Li, M.; Couture, L.; Hsu, D.; Forman, S. J.; Rossi, J. J.; Zaia, J. A. (2010).
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pre-transduced ex vivo with DDRNAI constructs using lentiviral vectors. This construct was designed to express three therapeutic RNAs, one of which was a shRNA, thereby combating HIV replication in three different ways:
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Unintended silencing of genes that share sequence homology with expressed shRNAs can theoretically occur. Careful selection of shRNA sequences and thorough preclinical testing of constructs can circumvent this issue.
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discussed above, the Center for
Infection and Immunity Amsterdam (CINIMA), the University of Amsterdam, the Netherlands, is extensively researching the composition of multi-cassette DNA constructs to tackle HIV.
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Zou, W.; Song, Z.; Guo, Q.; Liu, C.; Zhang, Z.; Zhang, Y. (2011). "Intrathecal
Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates Chronic Constriction Injury–Induced Neuropathic Pain in Rats".
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Jackson, A. L.; Bartz, S. R.; Schelter, J.; Kobayashi, S. V.; Burchard, J.; Mao, M.; Li, B.; Cavet, G.; Linsley, P. S. (2003). "Expression profiling reveals off-target gene regulation by RNAi".
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McBride, J. L.; Boudreau, R. L.; Harper, S. Q.; Staber, P. D.; Monteys, A. M.; Martins, I.; Gilmore, B. L.; Burstein, H.; Peluso, R. W.; Polisky, B.; Carter, B. J.; Davidson, B. L. (2008).
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Some gene therapy vectors integrate into the host genome, thereby acting as insertional mutagens. This was a particular issue with early retroviral vectors where insertions adjacent to
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Millington-Ward, S.; Chadderton, N.; O'Reilly, M.; Palfi, A.; Goldmann, T.; Kilty, C.; Humphries, M.; Wolfrum, U.; Bennett, J.; Humphries, P.; Kenna, P. F.; Farrar, G. J. (2011).
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This mechanism has been demonstrated to work as a novel therapeutic technique to silence disease-causing genes across a range of disease models, including viral diseases such as
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High-level expression of shRNAs has been shown to be toxic. Strategies to minimize levels of shRNA expression or promote precise processing of shRNAs can overcome this problem.
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Chen, C. -C.; Chang, C. -M.; Sun, C. -P.; Yu, C. -P.; Wu, P. -Y.; Jeng, K. -S.; Hu, C. -P.; Chen, P. -J.; Wu, J. -C.; Shih, C. H.; Gershwin, M. E.; Tao, M. -H. (2011).
1143:"Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibers"
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Please remove or replace such wording and instead of making proclamations about a subject's importance, use facts and attribution to demonstrate that importance.
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683:"RNA-Based Gene Therapy for HIV with Lentiviral Vector-Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma"
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delivery of DDRNAI constructs has been demonstrated using a range of vectors and reagents with different routes of administration (ROA).
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machinery continually manufactures the encoded RNAs. The shRNA molecules are then processed by endogenous systems before entering the
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Wang, G. P.; Levine, B. L.; Binder, G. K.; Berry, C. C.; Malani, N.; McGarrity, G.; Tebas, P.; June, C. H.; Bushman, F. D. (2009).
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1083:"Engineering HIV-1-Resistant T-Cells from Short-Hairpin RNA-Expressing Hematopoietic Stem/Progenitor Cells in Humanized BLT Mice"
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Ongoing expression of the shRNA has been confirmed in T cells, monocytes, and B cells more than one year after transplantation.
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1292:"Analysis of Lentiviral Vector Integration in HIV+ Study Subjects Receiving Autologous Infusions of Gene Modified CD4+ T Cells"
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Liu, Y. P.; Westerink, J. T.; Brake, O.; Berkhout, B. (2011). "RNAi-Inducing
Lentiviral Vectors for Anti-HIV-1 Gene Therapy".
415:) demonstrated that beta III-tubulin knockdown by DDRNAI delayed tumor growth and increased chemosensitivity in mouse models.
984:"Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa"
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Figure 2 illustrates the most common type of DDRNAI DNA construct, designed to express a shRNA. This figure consists of a
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1399:"Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi"
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Delivery of DDRNAI DNA constructs is simplified by the existence of several clinically approved and well-characterized
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resulted in the development of lymphoid tumors. AAV vectors are considered low-risk for host-genome integration, as
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or reagent tailored to target specific cells. Inside the cell, the DNA is transported to the nucleus where
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1033:"The Loop Position of shRNAs and Pre-miRNAs is Critical for the Accuracy of Dicer Processing In Vivo"
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Brake, O. T.; Hooft, K. 'T.; Liu, Y. P.; Centlivre, M.; Jasmijn Von Eije, K.; Berkhout, B. (2008).
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Lambeth, L. S.; Smith, C. A. (2013). "Short
Hairpin RNA-Mediated Gene Silencing".
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Nervana is an investigational V construct that knocks down the expression of
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Woods, N. B.; Bottero, V.; Schmidt, M.; Von Kalle, C.; Verma, I. M. (2006).
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Figure 1: A DDRNAI construct encoding a shRNA is packaged into a delivery
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DDRNAI constructs have also been successfully delivered into host cells
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634:. Methods in Molecular Biology. Vol. 942. pp. 205–232.
583:. Methods in Molecular Biology. Vol. 721. pp. 293–311.
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411:. Investigations by the Children's Cancer Institute Australia (
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Hepbarna, is under preclinical development for delivery by an
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TAR decoy RNA, inhibiting initiation of viral transcription.
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shRNA, that silences the tat and rev genes of the HIV genome
548:. Methods in Enzymology. Vol. 392. pp. 405–419.
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vector, jetPEI, that targets lung tissue are in progress.
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The development of resistance to chemotherapies such as
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to show a propensity to activate oncogene expression.
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use either viral vectors or one of several classes of
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A major contributor to this article appears to have a
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1235:"Gene therapy: Therapeutic gene causing lymphoma"
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520:Toxic effects due to over-expression of shRNAs
413:University of NSW, Lowy Cancer Research Centre
331:For example, in phase I clinical trial at the
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328:, and then transplanted back into the host.
130:promotes the subject in a subjective manner
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464:Besides the ex vivo approach by the
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132:without imparting real information
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745:(1): 25–33.
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739:Gene Therapy
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33:Please help
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1340:J. (2008).
226:lung cancer
222:hepatitis C
218:hepatitis B
1540:Stem cells
1499:Categories
615:References
397:paclitaxel
313:reagents.
36:improve it
491:oncogenes
401:cisplatin
142:June 2014
92:June 2014
84:talk page
42:talk page
1486:24778534
1478:12754523
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842:(2010).
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572:15644195
460:HIV/AIDS
300:Delivery
278:promoter
209:target.
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