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WO 2007/033436 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 29 March 2007 (29.03.2007) PCT WO 2007/033436 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (21) International Application Number: CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, PCT/AU2006/00 1402 GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, (22) International Filing Date: LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, 26 September 2006 (26.09.2006) NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 2005905307 26 September 2005 (26.09.2005) AU ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (71) Applicant (for all designated States except US): THE FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, UNIVERSITY OF QUEENSLAND [AU/AU]; St. Lu RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, cia, Queensland 4072 (AU). GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and Published: (75) Inventor/Applicant (for US only): CARROLL, Bernard — with international search report [AU/AU]; 8/142 Ryan Street, West End, Brisbane (AU). For two-letter codes and other abbreviations, refer to the "G uid (74) Agents: HUGHES, E, John, L. et al.; Davies Collison ance Notes on Codes and Abbreviations" appearing at the beg in Cave, 1 Nicholson Street, Melbourne, Victoria 3000 (AU). ning of each regular issue of the PCT Gazette. (54) Title: MODULATION OF GENE EXPRESSION AND AGENTS USEFUL FOR SAME (57) Abstract: The present invention relates generally to the field of gene expression, and particularly to the modulation of gene expression by a combination of double-stranded RNA and single-stranded sense RNA molecules targeted to the same gene. The invention also provides use of the methods for modulating gene expression in manipulating phenotypes and traits MODULATION OF GENE EXPRESSION AND AGENTS USEFUL FOR SAME BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates generally to the field of gene expression and more particularly the modulation of gene expression by transcriptional and post-transcriptional gene silencing mechanisms. Even more particularly, the present invention provides agents and protocols for modulating gene expression and their use in manipulating phenotypes and traits. DESCRIPTION OF THE PRIOR ART Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in any country. Gene silencing is an important tool in molecular biology and genetic engineering. There is great potential to generate genetically modified plants and animals which exhibit altered phenotypes having commercially or therapeutically useful properties. Some success has already been achieved in generating genetically modified plants and animals. However, gene silencing, and in particular targeted gene silencing is not always consistently successful or effective. In eukaryotic organisms, gene silencing via RNA interference (RNAi) is triggered by double-stranded RNA (dsRNA) and requires members of a relatively conserved set of gene products. dsRNA is processed by DICER and DICER-like (DCL) proteins into small interfering RNA (siRNA), 20-25 nucleotides in length. These small RNA then guide an RNA-initiated silencing complex (RISC) to mediate post-transcriptional gene silencing (PTGS) of niRNA and RNA viruses, or transcriptional gene silencing (TGS) of transposons and repetitive DNA. Key and perhaps autonomous components of RISCs are members of the ARGONAUTE family of proteins. In plants, a new class of nuclear DNA- dependent RNA polymerase (Pol IV), as well as RNA-dependent RNA polymerases (RDRs) have also been shown to be important components of PTGS and/or methylation of transposons and repetitive DNA. NRPDIa, which encodes a large subunit of Pol IVa, is so far unique in that mutants show both partial loss of PTGS and TGS of certain transposons and repetitive sequences. An intriguing feature of PTGS in plants and worms is that it can be systemically transmitted throughout the organism. When dsRNA is expressed or injected in one tissue of the organism, PTGS spreads to other tissues. The mobile signals are likely to be nucleic acids since systemic silencing is highly sequence-specific. One gene has been identified in C. elegans that is required for systemic spreading of PTGS called SID-I which encodes a transmembrane protein involved in transport of dsRNA. However, there is no SID-I gene in Arabidopsis and no other genes required for long-distance transmission of PTGS have yet been identified in plants. Given the importance of gene silencing in the genetic manipulation of cells and viral genomes, there is a need to improve targeted gene silencing techniques. SUMMARY OF THE INVENTION The present invention provides an enhanced method of inhibiting expression of a target gene including a viral genome in a cell by subjecting the gene to both RNA-directed transcriptional gene silencing (TGS) and RNAi-mediated post-transcriptional gene silencing (PTGS). A "gene" in this context is any nucleotide sequence which is subject to transcription or potential transcription and includes all or part of a viral genome. In addition, or in the alternative, one or more components of either the TGS or PTGS pathway may be up-regulated or otherwise targeted to facilitate target gene silencing. The method and agents of the present invention are useful in manipulating phenotypes and traits in plants and animals and can facilitate genetic therapy, maintenance and regeneration. The essence of the instant invention lies in part in the ability to stimulate both TGS and PTGS via nuclear RNA signaling. The RNA signal corresponds to an RNA silencing species comprising a single stranded (ss) or double stranded (ds) RNA molecule which may be DNA-derived or synthetic. Examples of RNA silencing species include short or long ds-RNA molecules, hairpin species and partial hairpin species which comprise a strand having a nucleotide sequence capable of hybridizing or forming a complex with a DNA strand of the target gene. The target gene in this instance refers to the actual target gene as well as introduced homologous target sequence. This leads to transcriptional gene silencing via a pathway involving RNA polymerase IV (Pol IV), RNA-dependent RNA polymerase 2 (RDR2), DICER-like3 (DCL3), ARGONAUTE4 (AGO4) and RDR6. Although not intending to limit the present invention to any theory or mode of action, it is proposed in a preferred embodiment that the RNA silencing species and the target gene (actual and/or homologous) or a transcript thereof lead to a synergistic effect in relation to inhibition of gene expression. In addition, the RNA silencing species may be produced in the same cell as the target gene or homologous target sequence or produced in a differenT-cell or introduced to a subject wherein it enters the cell carrying the target gene or homologous sequence. Hence, local (same cell, i.e. intra-cell) or remote (long distance, i.e. inter-cell) RNA signaling forms part of the present invention. RNAi is triggered by dsRNA which is processed by DICER and DICER-like proteins into small interfering RNA (siRNA). These small RNA guide an RNA-initiated silencing complex (RISC) to mediate PTGS of target transcript. As indicated above, the RNA silencing species may be generated in the same cell or a differenT-cell as the target gene. Consequently, short and long distance (i.e. cell autonomous and non-cell autonomous) RNA silencing is contemplated by the present invention. Accordingly, one aspect of the present invention contemplates a method of inhibiting expression of a target gene in a cell said method comprising: (i) introducing into or generating in said cell or parent or relative including progeny of said cell an RNA silencing species comprising a nucleotide sequence substantially homologous to all or part of a strand of said target gene; (ii) generating in said cell or a relative including progeny of said cell a transcript corresponding to all or part of the coding strand or other transcribed portion of said target gene; wherein inhibition of expression of the target gene occurs via transcriptional and post- transcriptional gene silencing. The present invention is not to be construed as being limited to any particular order of steps (i) and (ii). Hence, step (ii) may occur first or simultaneous with step (i). In addition, one or other of the step (i) or (ii) may occur through conventional breeding. As indicated above, this aspect of the present invention covers both intra-cellular and inter¬ cellular RNA signalling. In other words, the RNA silencing species may be generated in the same cell as the target gene or homologous target sequence or in a differenT-cell. The RNA transcript in part (ii) comprises at least 5 contiguous nucleotides homologous to the transcript of the actual target gene and is referred to as the "homologous target sequence".
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