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Matched Legal Cases: ['art 1', 'Application No. 2009', 'Application No. 2009', 'Application No. 2009', 'Application No. 2009', 'Application No. 10066344', 'Application No. 2007', 'Application No. 2007', 'Application No. 2007', 'Application No. 32713', 'Application No. 778474', 'Application No. 2005201044', 'Application No. 2005201044', 'art 1']

Patent US8202980 - Antisense oligonucleotide for use in prevention and treatment of viral and ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsThe present invention provides methods and compositions for inhibiting gene expression using double stranded RNA molecules that are between 15 and 21 nucleotides in length and are complementary to a target gene sequence....http://www.google.com/patents/US8202980?utm_source=gb-gplus-sharePatent US8202980 - Antisense oligonucleotide for use in prevention and treatment of viral and tumor disorders; gene expression inhibition; RNA interferenceAdvanced Patent SearchPublication numberUS8202980 B2Publication typeGrantApplication numberUS 10/612,179Publication dateJun 19, 2012Filing dateJul 2, 2003Priority dateJan 30, 1999Also published asCA2359180A1, CA2359180C, DE10066235B4, DE10080167B4, DE10080167D2, DE19956568A1, DE20023125U1, DE20023125U8, DE50000414D1, DE50010528D1, DE50015501D1, EP1144623A1, EP1144623B1, EP1144623B9, EP1214945A2, EP1214945A3, EP1214945B1, EP1550719A1, EP1550719B1, EP1798285A1, EP2363479A1, US8101584, US8101742, US8114851, US8114981, US8119608, US8168776, US8183362, US8729037, US20040053875, US20040072779, US20040102408, US20050100907, US20080166800, US20080171861, US20080171862, US20080182981, US20080233651, US20080261303, US20130164366, US20130164843, US20130177631, US20140051166, WO2000044895A1Publication number10612179, 612179, US 8202980 B2, US 8202980B2, US-B2-8202980, US8202980 B2, US8202980B2InventorsRoland Kreutzer, Stefan LimmerOriginal AssigneeAlnylam Pharmaceuticals, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (105), Non-Patent Citations (538), Referenced by (1), Classifications (29), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetAntisense oligonucleotide for use in prevention and treatment of viral and tumor disorders; gene expression inhibition; RNA interferenceUS 8202980 B2Abstract The present invention provides methods and compositions for inhibiting gene expression using double stranded RNA molecules that are between 15 and 21 nucleotides in length and are complementary to a target gene sequence.
BACKGROUND OF THE INVENTION Field of the Invention The present invention is in the field of inhibition of gene expression using double stranded oligoribonuclcotides.
DE 196 31 919 C2 describes an antisense RNA with specific secondary structures, the antisense RNA being present in the form of a vector encoding it. The antisense RNA takes the form of an RNA molecule which is complementary to regions of the mRNA. Inhibition of the gene expression is caused by binding to these regions. This inhibition can be employed in particular for the diagnosis and/or therapy of diseases, for example tumor diseases or viral infections.�The disadvantage is that the antisense RNA must be introduced into the cell in an amount which is at least as high as the amount of the mRNA. The known antisense methods are not particularly effective.
BRIEF SUMMARY OF THE INVENTION The present invention provides methods and compositions for inhibiting gene expression using double stranded RNA molecules as well as double stranded RNA molecules containing modified bases.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the schematic representation of a plasmid for the in vitro transcription with T7- and SP6-polymerase.
DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to do away with the disadvantages of the prior art. In particular, it is intended to provide as effective as possible a method, medicament or use for the preparation of a medicament, which method, medicament or use is capable of causing particularly effective inhibition of the expression of a given target gene.
It has proved advantageous for the dsRNA or the vector to be present packaged into micellar structures, preferably in liposomes. The dsRNA or the vector can likewise be enclosed in viral natural capsids or in chemically or enzymatically produced artificial capsids or structures derived therefrom.�The above-mentioned features make it possible to introduce the dsRNA or the vector into given target cells.
A further especially advantageous embodiment provides that the dsRNA or the vector is bound to, associated with or surrounded by, at least one viral coat protein which originates from a virus, is derived therefrom or has been prepared synthetically. The coat protein can be derived from polyomavitus. The coat protein can contain the polyomavirus virus protein 1 (VP1) and/or virus protein 2 (VP2). The use of such coat proteins is known from, for example, DE 196 18 797 A1, whose disclosure is herewith incorporated.�The abovementioned features considerably facilitate the introduction of the dsRNA or of the vector into the cell.
The invention furthermore provides a medicament with at least one oligoribonucleotide with double-stranded structure (dsRNA) for inhibiting the expression of a given target gene, where one strand of the dsRNA has a region I where at least segments are complementary to the target gene.�Surprisingly, it has emerged that such a dsRNA is suitable as medicament for inhibiting the expression of a given gene in mammalian cells. In comparison with the use of single-stranded oligoribonucleotides, the inhibition is already caused at concentrations which are lower by at least one order of magnitude. The medicament according to the invention is highly effective. Lesser side effects can be expected.
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 �Taq 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 Tag 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 1 191 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.
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 [�-32 P]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 12 000 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 12 000 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.
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