Source: http://www.google.com/patents/US8101742?dq=6317900
Timestamp: 2018-01-19 06:05:25
Document Index: 41485153

Matched Legal Cases: ['art 1', 'Application No. 2009', 'Application No. 2009', 'Application No. 2007', 'Application No. 2007', 'Application No. 2007', 'Application No. 32713', 'Application No. 2005201044', 'Application No. 2005201044', 'art 1']

Patent US8101742 - Method and medicament for inhibiting the expression of a given gene - Google Patents
The invention relates to an isolated RNA that mediates RNA interference of an mRNA to which it corresponds and a method of mediating RNA interference of mRNA of a gene in a cell or organism using the isolated RNA....http://www.google.com/patents/US8101742?utm_source=gb-gplus-sharePatent US8101742 - Method and medicament for inhibiting the expression of a given gene
Publication number US8101742 B2
Application number US 11/982,305
Also published as CA2359180A1, CA2359180C, DE10066235B4, DE10066235C5, DE10080167B4, DE10080167D2, DE19956568A1, DE20023125U1, DE20023125U8, DE50000414D1, DE50010528D1, DE50015501D1, EP1144623A1, EP1144623B1, EP1144623B9, EP1214945A2, EP1214945A3, EP1214945B1, EP1550719A1, EP1550719B1, EP1798285A1, EP1798285B1, EP2363479A1, EP2363479B1, EP3018207A1, US8101584, US8114851, US8114981, US8119608, US8168776, US8183362, US8202980, US8729037, US8877726, US9133454, US20040053875, US20040072779, US20040102408, US20050100907, US20080166800, US20080171861, US20080171862, US20080182981, US20080233651, US20080261303, US20130164366, US20130164843, US20130177631, US20140051166, US20140220113, US20140220676, WO2000044895A1
Publication number 11982305, 982305, US 8101742 B2, US 8101742B2, US-B2-8101742, US8101742 B2, US8101742B2
Patent Citations (153), Non-Patent Citations (545), Referenced by (8), Classifications (24), Legal Events (4)
US 8101742 B2
The plasmid shown in FIG. 1 was constructed for use in the enzymatic synthesis of the dsRNA. To this end, a polymerase chain reaction (PCR) with the “positive control DNA” of the HelaScribe® Nuclear Extract in vitro transcription kit by Promega, Madison, USA, as DNA template was first carried out. One of the primers used contained the sequence of an EcoRI cleavage site and of the T7 RNA polymerase promoter as shown in sequence listing No. 1. The other primer contained the sequence of a BamHI cleavage site and of the SP6 RNA polymerase promoter as shown in sequence listing No. 2. In addition, the two primers had, at the 3′ ends, regions which were identical with or complementary to the DNA template. The PCR was carried out by means of the “Tag PCR Core Kits” by Qiagen, Hilden, Germany, following the manufacturer's instructions. 1.5 mM MgCl2, in each case 200 μM dNTP, in each case 0.5 μM primer, 2.5 U Taq DNA polymerase and approximately 100 ng of “positive control DNA” were employed as template in PCR buffer in a volume of 100 μl. After initial denaturation of the template DNA by heating for 5 minutes at 94° C., amplification was carried out in 30 cycles of denaturation for in each case 60 seconds at. 94° C., annealing for 60 seconds at 5° C. below the calculated melting point of the primers and polymerization for 1.5-2 minutes at 72° C. After a final polymerization of 5 minutes at 72° C., 5 μl of the reaction were analyzed by agarose-gel electrophoresis. The length of the DNA fragment amplified thus was 400 base pairs, 340 base pairs corresponding to the “positive control DNA”. The PCR product was purified, hydrolyzed with EcoRI and BamHI and, after repurification, employed in the ligation together with a pUC18 vector which had also been hydrolyzed by EcoRI and BamHI. E. coli XL1-blue was then transformed. The plasmid obtained (pCMV5) carries a DNA fragment whose 5′ end is flanked by the T7 promoter and whose 3′ end is flanked by the SP6 promoter. By linearizing the plasmid with BamHI, it can be employed in vitro with the T7-RNA polymerase for the run-off transcription of a single-stranded RNA which is 340 nucleotides in length and shown in sequence listing No. 3. If the plasmid is linearized with EcoRI, it can be employed for the run-off transcription with SP6 RNA polymerase, giving rise to the complementary strand. In accordance with the method outlined hereinabove, an RNA 23 nucleotides in length was also synthesized. To this end, a DNA shown in sequence listing No. 4 was ligated with the pUC18 vector via the EcoRI and BamHI cleavage sites.
Plasmid pCMV1200 was constructed as DNA template for the in-vitro transcription with HeLa nuclear extract. To this end, a 1191 bp EcoRI/BamHI fragment of the positive control DNA contained in the HeLaScribe® Nuclear Extract in vitro transcription kit was amplified by means of PCR. The amplified fragment encompasses the 828 bp “immediate early” CMV promoter and a 363 bp transcribable DNA fragment. The PCR product was ligated to the vector pGEM-T via “T-overhang” ligation. A BamHI cleavage site is located at the 5′ end of the fragment. The plasmid was linearized by hydrolysis with BamHI and used as template in the run-off transcription.
pCMV5 plasmid DNA was linearized with EcoRI or BamHI. It was used as DNA template for an in-vitro transcription of the complementary RNA single strands with SP6 and T7 RNA polymerase, respectively. The “Riboprobe in vitro Transcriptions” system by Promega, Madison, USA, was employed for this purpose. Following the manufacturer's instructions, 2 μg of linearized plasmid DNA were incubated in 100 μl of transcription buffer and 40 U T7 or SP6 RNA polymerase for 5-6 hours at 37° C. The DNA template was subsequently degraded by addition of 2.5 μl of RNase-free DNase RQ1 and incubation for 30 minutes at 37° C. The transcription reaction was made up to 300 μl with H2O and purified by phenol extraction. The RNA was precipitated by addition of 150 μl of 7 M ammonium acatate [sic] and 1125 μl of ethanol and stored at −65° C. until used for the hybridization.
For the hybridization, 500 μl of the single-stranded RNA which had been stored in ethanol and precipitated were spun down The resulting pellet was dried and taken up in 30 μl of PIPES buffer, pH 6.4 in the presence of 80% for amide, 400 mM NaCl and 1 mM EDTA. In each case 15 μl of the complementary single strands were combined and heated for 10 minutes at 85° C. The reactions were subsequently incubated overnight at 50° C. and cooled to room temperature.
Only approximately equimolar amounts of the two single strands were employed in the hybridization. This is why the dsRNA preparations contained single-stranded RNA (ssRNA) as contaminant. In order to remove these ssRNA contaminants, the reactions were treated, after hybridization, with the single-strand-specific ribonucleases bovine pancreatic RNase A and Aspergillus oryzae RNase T1. RNase A is an endoribonuclease which is specific for pyrimidines. RNase T1 is an endoribonuclease which preferentially cleaves at the 3? side of guanosines. dsRNA is no substrate for these ribonucleases. For the RNase treatment, the reactions in 300 μl of Tris, pH 7.4, 300 mM NaCl and 5 mM EDTA were treated with 1.2 μl of RNaseA at a concentration of 10 mg/ml and 2 μl of RNaseT1 at a concentration of 290 μg/ml. The reactions were incubated for 1.5 hours at 30° C. Thereupon, the RNases were denatured by addition of 5 μl of proteinase K at a concentration of 20 mg/ml and 10 μl of 20% SDS and incubation for 30 minutes at 37° C. The dsRNA was purified by phenol extraction and precipitated with ethanol. To verify the completeness of the RNase digestion, two control reactions were treated with ssRNA analogously to the hybridization reactions.
Using the HeLaScribe® Nuclear Extract in vitro transcription kit by Promega, Madison, USA, the transcription efficiency of the abovementioned DNA fragment which is present in plasmid pCMV1200 and homologous to the “positive control DNA” was determined in the presence of the dsRNA (dsRNA-CMV5) with sequence homology. Also, the effect of the dsRNA without sequence homology, which corresponds to the yellow fluorescent protein (YFP) gene (dsRNA-YRP), was studied. This dsRNA had been generated analogously to the dsRNA with sequence homology. The sequence of a strand of this dsRNA can be found in sequence listing No. 5. Plasmid pCMV1200 was used as template for the run-off transcription. It carries the “immediate early” cytomegalovirus promoter which is recognized by the eukaryotic RNA polymerase II, and a transcribable DNA fragment. Transcription was carried out by means of the HeLa nuclear extract, which contains all the proteins which are necessary for transcription. By addition of [•−32P]rGTP to the transcription reaction, radiolabeled transcript was obtained. The [•−32P]rGTP used had a specific activity of 400 Ci/mmol, 10 mCi/ml. 3 mM MgCl2, in each case 400 μM rATP, rCTP, rUTP, 16 μM rGTP, 0.4 μM [•−32P]rGTP and depending on the experiment 1 fmol of linearized plasmid DNA and various amounts of dsRNA in transcription buffer were employed per reaction. Each batch was made up to a volume of 8.5 μl with H2O. The reactions were mixed carefully. To start the transcription, 4 U HeLa nuclear extract in a volume of 4 μl were added and incubated for 60 minutes at 30° C. The reaction was stopped by addition of 87.5 μl of quench mix which had been warmed to 30° C. To remove the proteins, the reactions were treated with 100 μl of phenol/chloroform/isoamyl alcohol (25:24:1 v/v/v) saturated with TE buffer, pH 5.0, and the reactions were mixed vigorously for 1 minute. For phase separation, the reactions were spun for approximately 1 minute at 12000 rpm and the top phase was transferred into a fresh reaction vessel. Each reaction was treated with 250 μl of ethanol. The reactions were mixed thoroughly and incubated for at least 15 minutes on dry ice/methanol. To precipitate the RNA, the reactions were spun for 20 minutes at 12000 rpm and 40° C. The supernatant was discarded. The pellet was dried in vacuo for 15 minutes and resuspended in 10 μl of H2O. Each reaction was treated with 10 μl of denaturing loading buffer. The free GTP was separated from the transcript formed by means of denaturing polyacrylamide gel electrophoresis on an 8% gel with 7 M urea. The RNA transcripts formed upon transcription with HeLa nuclear extract, in denaturing loading buffer, were heated for 10 minutes at 90° C. and 10 μl aliquots were applied immediately to the freshly washed pockets. The electrophoresis was run at 40 mA. The amount of the radioactive ssRNA formed upon transcription was analyzed after electrophoresis with the aid of an Instant Imager.
For the microinjection, the culture dishes were removed from the incubator for approximately 10 minutes. Approximately 50 nuclei were injected singly per reaction within a marked area using the AIS microinjection system from Carl Zeiss, Göttingen, Germany. The cells were subsequently incubated for three more hours. For the microinjection, borosilicate glass capillaries from Hilgenberg GmbH, Malsfeld, Germany, with a diameter of less than 0.5 μm at the tip were prepared. The microinjection was carried out using a micromanipulator from Narishige Scientific Instrument Lab, Tokyo, Japan. The injection time was 0.8 seconds and the pressure was approximately 100 hPa. The transfection was carried out using the plasmid PcDNA YFP, which contains an approximately 800 bp BamHI/EcoRI fragment with the YFP gene in vector pcDNA3. The samples injected into the nuclei contained 0.01 μg/μl of pCDNA-YFP and Texas Red coupled to dextran-70000 in 14 mM NaCl, 3 mM KCl, 10 mM KPO4 [sic], ph 7.5. Approximately 100 pl of RNA with a concentration of 1 μM or, in the case of the L-dsRNA, 375 μM were additionally added.
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International Classification A61K31/70, A61K38/00, C12N15/11, C07H21/04, A61K35/76, C12N15/09, A61K48/00, A61K9/127, A61K31/713, A61P31/12, A61P25/28, A61P35/00, A61K47/48
Cooperative Classification C12N15/111, C12N2310/111, C12N2310/53, A61K38/00, C12N2310/14, A61K31/713, C12N2330/30, C12N15/113
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