WO2004042024A2 - COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF HIF-1 ALPHA - Google Patents
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Definitions
- Hypoxia-inducible factor 1 is a heterodimeric basic-helix-loop-helix- PAS transcription factor consisting of HIF-l alpha and HIF-l beta subunits. HIF-l alpha expression and FHF-1 transcriptional activity increase exponentially as cellular oxygen concentration is decreased. Several dozen target genes that are transactivated by HIF-l have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and NEGF. Semenza GL (1999), Ann. Rev. Cell. Dev. Biol. 15: 551-578.
- the present invention is directed to siR ⁇ As which specifically target and cause R ⁇ Ai- induced degradation of mR ⁇ A from the human HIF-l alpha gene.
- the siR ⁇ A compounds and compositions of the invention are used to treat cancerous tumors and other angiogenic diseases and non-pathogenic conditions in which NEGF is overexpressed in tissues in or near the area of neovascularization.
- the invention provides siR ⁇ A, and pharmaceutical compositions thereof, which target HIF-l alpha mR ⁇ A and induce R ⁇ Ai-mediated degradation of the targeted mR ⁇ A.
- the invention further provides a method of inhibiting expression of HIF-l alpha, comprising administering to a subject an effective amount of an siR ⁇ A targeted to HIF-l alpha mR ⁇ A, such that the HIF-l alpha mR ⁇ A is degraded.
- the respective 21-nt sense and antisense strands of this embodiment therefore generally begin with a purine nucleotide.
- siRNA can be expressed from pol III expression vectors without a change in targeting site, as expression of RNAs from pol III promoters is only believed to be efficient when the first transcribed nucleotide is a purine.
- the sense strand of the present siRNA comprises a nucleotide sequence identical to any contiguous stretch of about 19 to about 25 nucleotides in the target mRNA.
- Suitable AAN vectors for expressing the siR ⁇ A of the invention methods for constructing the recombinant AAN vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher KJ et al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989j, J. Virol. 63: 3822-
- R Ai-mediated degradation of target mR ⁇ A by an siR ⁇ A containing a given target sequence can also be evaluated with animal models of neovascularization, such as the retinopathy of prematurity ("ROP") or choroidal neovascularization ("C ⁇ V”) mouse models.
- ROP retinopathy of prematurity
- C ⁇ V choroidal neovascularization
- areas of neovascularization in an ROP or C ⁇ N mouse can be measured before and after administration of an siR ⁇ A. A reduction in the areas of neovascularization in these models upon administration of the siR ⁇ A indicates the down-regulation of the target mR ⁇ A (see Example 2 below).
- an siRNA of the invention is used to inhibit choroidal neovascularization in age-related macular degeneration.
- the present siRNA can be administered to the subject either as naked siRNA, in conjunction with a delivery reagent, or as a recombinant plasmid or viral vector which expresses the siRNA.
- Suitable delivery reagents for administration in conjunction with the present siRNA include the Minis Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; or polycations (e.g., polylysine), or liposomes.
- a preferred delivery reagent is a liposome.
- Liposomes can aid in the delivery of the siRNA to a particular tissue, such as retinal or tumor tissue, and can also increase the blood half-life of the siRNA.
- Liposomes suitable for use in the invention are formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors such as the desired liposome size and half-life of the liposomes in the blood stream. A variety of methods are known for preparing liposomes, for example as described in Szoka et al. (1980), Ann. Rev. Biophys. Bioeng. 9: 467; and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire disclosures of which are herein incorporated by reference.
- the liposomes encapsulating the present siRNA comprise a ligand molecule that can target the liposome to a particular cell or tissue at or near the site of angiogenesis.
- Ligands which bind to receptors prevalent in tumor or vascular endothelial cells such as monoclonal antibodies that bind to tumor antigens or endothelial cell surface antigens, are preferred.
- opsonization-inhibiting hydrophilic polymers form a protective surface layer which significantly decreases the uptake of the liposomes by the macrophage-monocyte system ("MMS") and reticuloendothelial system ("RES"); e.g., as described in U.S. Pat. No. 4,920,016, the entire disclosure of which is herein incorporated by reference.
- MMS macrophage-monocyte system
- RES reticuloendothelial system
- liposomes of the invention that are modified with opsonization-inhibition moieties can deliver the present siRNA to tumor cells.
- Opsonization inhibiting moieties suitable for modifying liposomes are preferably water-soluble polymers with a number-average molecular weight from about 500 to about 40,000 daltons, and more preferably from about 2,000 to about 20,000 daltons.
- Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; e.g., methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric polyamidoamines; polyacrylic acids; polyalcohols, e.g., polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GMi.
- PEG polyethylene glycol
- PPG polypropylene glycol
- synthetic polymers such as polyacrylamide or poly N-vin
- the opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, e.g., galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; aminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, e.g., reacted with derivatives of carbonic acids with resultant linking of carboxylic groups.
- natural polysaccharides containing amino acids or carboxylic acids e.g., galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan
- aminated polysaccharides or oligosaccharides linear or branched
- the opsonization inhibiting moiety can be bound to the liposome membrane by any one of numerous well-known techniques.
- an N- hydroxysuccinimide ester of PEG can be bound to a phosphatidyl-ethanolamine lipid- soluble anchor, and then bound to a membrane.
- a dextran polymer can be derivatized with a stearylamine lipid-soluble anchor via reductive amination using Na(CN)BH 3 and a solvent mixture such as tetrahydrofuran and water in a 30: 12 ratio at 60 °C.
- the siRNA of the invention can be administered to the subject by any means suitable for delivering the siRNA to the cells of the tissue at or near the area of neovascularization.
- the siRNA can be administered by gene gun, electroporation, or by other suitable parenteral or enteral administration routes.
- Suitable enteral administration routes include oral, rectal, or intranasal delivery.
- injections or infusions of the siRNA are given at or near the site of neovascularization.
- the siRNA of the invention can ⁇ 31- be delivered to retinal pigment epithelial cells in the eye.
- the siRNA is administered topically to the eye, e.g. in liquid or gel form to the lower eye lid or conjunctival cul-de-sac, as is within the skill in the art (see, e.g., Acheampong AA et al, 2002, Drug Metabol. and Disposition 30: 421-429, the entire disclosure of which is herein incorporated by reference).
- the siRNA of the invention is administered topically to the eye in volumes of from about 5 microliters to about 75 microliters, for example from about 7 microliters to about 50 microliters, preferably from about 10 microliters to about 30 microliters.
- the siRNA of the invention is highly soluble in aqueous solutions, It is understood that topical instillation in the eye of siRNA in volumes greater than 75 microliters can result in loss of siRNA from the eye through spillage and drainage.
- a high concentration of siRNA e.g., 100-1000 nM
- a particularly preferred parenteral administration route is intraocular administration.
- intraocular administration of the present siRNA can be accomplished by injection or direct (e.g., topical) administration to the eye, as long as the administration route allows the siRNA to enter the eye.
- suitable intraocular routes of administration include intravitreal, intraretinal, subretinal, subtenon, peri- and retro-orbital, trans-comeal and trans-scleral administration.
- intraocular administration routes are within the skill in the art; see, e.g., and Acheampong AA et al, 2002, supra; and Bennett et al. (1996), Hum. Gene Ther. 7: 1763-1769 and Ambati I et al., 2002, Progress in Retinal and Eye Res. 21: 145-151, the entire disclosures of which are herein incorporated by reference.
- the siRNA of the mvention can be administered in a single dose or in multiple doses.
- the infusion can be a single sustained dose or can be delivered by multiple infusions.
- Injection of the siRNA directly into the tissue is at or near the site of neovascularization preferred.
- Multiple injections of the siRNA into the tissue at or near the site of neovascularization are particularly preferred.
- One skilled in the art can also readily determine an appropriate dosage regimen for administering the siRNA of the invention to a given subject.
- the siRNA can be administered to the subject once, such as by a single injection or deposition at or near the neovascularization site.
- the siRNA can be administered to a subject multiple times daily or weekly.
- physiologically acceptable earner media are water, buffered water, saline solutions (e.g., normal saline or balanced saline solutions such as Hank's or Earle's balanced salt solutions), 0.4% saline, 0.3% glycine, hyaluronic acid and the like.
- compositions of the invention for topical intraocular delivery can comprise saline solutions as described above, corneal penetration enhancers, insoluble particles, petrolatum or other gel-based ointments, polymers which undergo a viscosity increase upon instillation in the eye, or mucoadhesive polymers.
- the intraocular delivery reagent increases corneal penetration, or prolongs preocular retention of the siRNA through viscosity effects or by establishing physicochemical interactions with the mucin layer covering the corneal epithelium.
- Suitable mucoadhesive polymers include hydrocoUoids with multiple hydrophilic functional groups such as carboxyl, hydroxyl, amide and/or sulfate groups; for example, hydroxypropylcellulose, polyacrylic acid, high-molecular weight polyethylene glycols (e.g., >200,000 number average molecular weight), dextrans, hyaluronic acid, polygalacturonic acid, and xylocan.
- Suitable corneal penetration enhancers include cyclodextrins, benzalkonium chloride, polyoxyethylene glycol lauryl ether (e.g., Brij® 35), polyoxyethylene glycol stearyl ether (e.g., Brij® 78), polyoxyethylene glycol oleyl ether (e.g., Brij® 98), ethylene diamine tetraacetic acid (EDTA), digitonin, sodium taurocholate, saponins and polyoxyethylated castor oil such as Cremaphor EL.
- polyoxyethylene glycol lauryl ether e.g., Brij® 35
- polyoxyethylene glycol stearyl ether e.g., Brij® 78
- polyoxyethylene glycol oleyl ether e.g., Brij® 98
- EDTA ethylene diamine tetraacetic acid
- digitonin sodium taurocholate
- saponins and polyoxyethylated cast
- a solid pharmaceutical composition for oral administration can comprise any of the carriers and excipients listed above and 10-95%>, preferably 25%- 75%, of one or more siRNA of the invention.
- a pharmaceutical composition for aerosol (inhalational) administration can comprise 0.01-20%) by weight, preferably 1%-10% by weight, of one or more siRNA of the invention encapsulated in a liposome as described above, and propellant.
- a earner can also be included as desired; e.g., lecithin for intranasal delivery.
- anti-MF-l alpha siRNAs contained the targeting sequences listed in Table 2, and all siRNAs contained 3' TT overhangs on each strand.
- the "sample #" listed in Table 2 corresponds to the experimental cell sample as indicated in Figs. 1 and 2.
- hypoxia was induced in control and experimental HEK-293 cells with desfemoxamine at a final concentration of 200 micromolar.
- the cell culture medium was removed from all wells and a human NEGF ELISA (R & D systems, Minneapolis, M ⁇ ) was performed as described in the Quantikine human NEGF ELISA protocol.
- ELISA results were read on an AD340 plate reader (Beckman Coulter), and are given in Fig. 1.
- human NEGF protein was upregulated in HEK- 293 cells by the desferrioxamine-mediated induction of hypoxia.
- hypoxia-induced increase in NEGF protein was reduced in cells transfected with the human anti-HIF-1 alpha siR ⁇ As.
- Transfections of hypoxic cells with non-specific siR ⁇ A (EGFP siR ⁇ A) or mock transfection without siR ⁇ A had no effect on NEGF protein levels.
- the anti-HIF-1 alpha siR ⁇ As hHIFl#12, hHIFl#13 and hHIFl#16 reduced NEGF protein expression to levels approaching that of non-hypoxic HEK-293 cells.
- Anti-HIF-1 alpha siR ⁇ A hHIFl#l 1 reduced NEGF protein expression to below that of non-hypoxic HEK-293 cells.
- a cytotoxicity assay was performed as follows. Complete growth medium containing 10% AlamarBlue (Biosource, Camarillo, CA) was added to each well, and the cells were incubated at 37°C with 5% CO 2 for 3 hours. Cell proliferation was measured by detecting the color change of medium containing AlamarBlue resulting from cell metaboHc activity. Cytotoxicity assay results were read on an AD340 plate reader (Beckman Coulter) and are given in Fig. 2. As can be seen from Fig. 2, none of the twenty anti-HIF-1 alpha siR ⁇ As tested showed significant cytotoxicity in the HEK-293 cells.
- the growth medium in each well was completely removed, and R ⁇ A extractions from the HEK-293 cells were performed with the R ⁇ Aqueous R ⁇ A isolation kit (Ambion, Austin, TX) according to the manufacturer's instructions.
- the levels of human HIF-l alpha and VEGF mR ⁇ A in the cells were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR), using the level of human glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) mR ⁇ A as an internal standard.
- RT-PCR quantitative reverse transcription-polymerase chain reaction
- VEGF mR ⁇ A levels of human VEGF were reduced by transfection with anti-HIF-1 alpha siR ⁇ As.
- Transfection of hypoxic cells with non-specific siR ⁇ A (EGFP siR ⁇ A) or mock transfection with no siR ⁇ A did not reduce VEGF mR ⁇ A levels.
- the introduction of anti-HIF-1 alpha siR ⁇ As into the HTK-293 cells induced the destruction of the VEGF mR ⁇ A, as compared to cells transfected with non-specific siRNA or no siRNA.
- the destruction of VEGF mRNA induced by the anti-HIF-1 alpha siRNAs correlated with the reduction in VEGF protein production shown in Fig. 1.
- siRNA targeted to mouse HIF-l alpha mRNA was delivered to both eyes of each animal in the test group by intravitreal injection. Control animals received intravitreal injection of carrier only.
- the target sequence of the mouse anti-HIF-1 alpha mRNA was AACTAACTGGACACAGTGTGT (SEQ ID NO: 297), and the siRNA used was:
- choroidal flat mount preparations Twelve days after laser photocoagulation, the animals were perfused with high molecular weight dextran-fluorescein (Molecular Probes, Eugene, OR) to label the retinal/choroidal vasculature, and the eyes were harvested. The area of each CNV was measured in choroidal flat mount preparations. To prepare choroidal flat mounts, the anterior chamber was removed and the retina was extracted with the vitreous, leaving the eyecup. Relaxing incisions were made on the eye cup and the choroid was flattened onto a slide.
- dextran-fluorescein Molecular Probes, Eugene, OR
- a masked investigator identified lesions in the dextran-fluorescein-perfused flat mount preparations as circular fluorescent (fluorescein positive) areas corresponding to the area previously exposed to the laser light. Images of the lesions were captured using a black and white Hamamatsu CCD camera (Hamamatsu Photonics, Bridgewater, NJ) coupled to a Apple Macintosh G4 computer (Cupertino, CA) equipped with OpenLab 2.2 software. Images for calibration were obtained from a slide with a grating of known size.
- the hyperfluorescent fluorescein-dextran labeled blood vessels within the area of the laser burn were selected as "region of interest” (ROI) using Openlab software, and this software was used to calculate the area ( ⁇ m 2 ) occupied by the white pixels in the ROIs.
- ROIs were selected after collecting the images under identical integration settings by using the Openlab "magic wand" tool to identify pixels in the laser burn site at a range of 2000-4090 intensity units, as defined within the Openlab software.
- the intensity units which were selected represented levels measured in normal fluorescein-perfused vasculature. For reference, the intensity of background, non- fluorescent areas was ⁇ 450 intensity units.
- the ROIs were generally well-circumscribed by a region lacking fluorescence.
- images were colorized in Openlab by applying an intensity ramp at 515 nanometers (the wavelength at which the image data were captured), using the "apply wavelength” function in the Openlab software. This intensity ramp was applied to all of the pixels in the image, and made the whitest pixels the brightest green color.
- the images were then exported to Adobe Photoshop software for presentation purposes. Situations in which there was no evidence of a laser burn after bright field analysis of choroidal flatmounts were excluded.
Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ540779A NZ540779A (en) | 2002-11-01 | 2003-10-31 | Compositions and methods for siRNA inhibition of HIF-1 alpha |
AU2003291678A AU2003291678B2 (en) | 2002-11-01 | 2003-10-31 | Compositions and methods for siRNA inhibition of HIF-1 alpha |
JP2004550399A JP5449639B2 (en) | 2002-11-01 | 2003-10-31 | Compositions and methods for siRNA inhibition of HIF-1 alpha |
CA2504926A CA2504926C (en) | 2002-11-01 | 2003-10-31 | Compositions and methods for sirna inhibition of hif-1 alpha |
MXPA05004722A MXPA05004722A (en) | 2002-11-01 | 2003-10-31 | COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF HIF-1 ALPHA. |
EP03768569A EP1562970A4 (en) | 2002-11-01 | 2003-10-31 | COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF HIF-1 ALPHA |
IL168224A IL168224A (en) | 2002-11-01 | 2005-04-25 | Sirna compositions for inhibition of hif-1 alpha |
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US42326202P | 2002-11-01 | 2002-11-01 | |
US60/423,262 | 2002-11-01 |
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---|---|---|---|---|
WO2005035759A2 (en) * | 2003-08-20 | 2005-04-21 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HYPOXIA INDUCIBLE FACTOR 1 (HIF1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
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WO2006050734A3 (en) * | 2004-11-09 | 2006-08-03 | Santaris Pharma As | Potent lna oligonucleotides for the inhibition of hif-1a expression |
WO2006083945A2 (en) * | 2005-02-01 | 2006-08-10 | Alcon, Inc. | Rnai-mediated inhibition of ocular targets |
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WO2007076351A2 (en) * | 2005-12-29 | 2007-07-05 | Alcon Research, Ltd. | Rnai-mediated inhibition of hif1a for treatment of ocular angiogenesis |
WO2007080902A1 (en) * | 2006-01-11 | 2007-07-19 | Kyowa Hakko Kogyo Co., Ltd. | Composition inhibiting the expression of target gene in eyeball and remedy for disease in eyeball |
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WO2008019254A2 (en) * | 2006-08-03 | 2008-02-14 | Warsaw Orthopedic, Inc. | Reagents, methods and systems to suppress pro-inflammatory cytokines |
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JP2008514242A (en) * | 2004-10-01 | 2008-05-08 | ノバルティス ヴァクシンズ アンド ダイアグノスティクス, インコーポレイテッド | Modified small interfering RNA molecules and methods of use |
JP2008517940A (en) * | 2004-10-22 | 2008-05-29 | サウス、アラバマ、メディカル、サイエンス、ファウンデーション | RNAi regulation of RSV, PIV and other respiratory viruses and uses thereof |
WO2008109381A2 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting hif1a gene expression and uses thereof |
JP2008543864A (en) * | 2005-06-15 | 2008-12-04 | ファイブローゲン、インコーポレーテッド | Compounds and methods for cancer treatment |
JP2009512673A (en) * | 2005-10-20 | 2009-03-26 | シレンティス・エセ・ア・ウ | Control of TRPV expression level |
WO2009039300A2 (en) * | 2007-09-18 | 2009-03-26 | Intradigm Corporation | Compositions comprising hif-1 alpha sirna and methods of use thereof |
WO2009156730A1 (en) * | 2008-06-25 | 2009-12-30 | University Court Of The University Of Dundee | Treatment of epithelial fragility disorders |
US7645744B2 (en) | 2002-11-01 | 2010-01-12 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of HIF-1 alpha |
WO2010043630A2 (en) * | 2008-10-13 | 2010-04-22 | Sigmoid Pharma Limited | A delivery system for rna |
EP2186528A1 (en) * | 2007-08-06 | 2010-05-19 | Senju Pharmaceutical Co., Ltd. | Pharmaceutical containing hif-1 alpha and hif-2 alpha expression inhibitor |
US7737264B2 (en) | 2002-04-05 | 2010-06-15 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation HIF-1α expression |
US7741299B2 (en) * | 2004-08-16 | 2010-06-22 | Quark Pharmaceuticals, Inc. | Therapeutic uses of inhibitors of RTP801 |
US7807650B2 (en) | 2005-03-14 | 2010-10-05 | Sylentis S.A.U. | Methods and compositions for the treatment of intestinal conditions |
FR2944437A1 (en) * | 2009-04-16 | 2010-10-22 | Oreal | Protecting/preventing cosmetic injurious effects induced by UVA radiation on skin of subject, comprises administering agent to inhibit transcription factor hypoxia-inducible factor-1 alpha, where agent is e.g. antibody or its fragment |
US7872119B2 (en) | 2007-02-26 | 2011-01-18 | Quark Pharmaceuticals, Inc. | Inhibitors of RTP801 and their use in disease treatment |
EP2363503A1 (en) * | 2002-11-23 | 2011-09-07 | ISIS Pharmaceuticals, Inc. | Modulation of HIF1A and HIF2A expression |
US8188057B2 (en) | 2005-10-25 | 2012-05-29 | Sylentis S.A.U. | Modulation of 11beta-hydroxysteriod dehydrogenase 1 expression for the treatment of ocular diseases |
US8318689B2 (en) | 2001-11-09 | 2012-11-27 | Centre National De La Recherche Scientifique | SiRNA-based cancer treatment |
US8598134B2 (en) | 2004-10-22 | 2013-12-03 | South Alabama Medical Science Foundation | RNAi modulation of RSV, PIV and other respiratory viruses and uses thereof |
KR101390966B1 (en) | 2010-12-30 | 2014-06-30 | 주식회사 삼양바이오팜 | siRNA for inhibition of Hif1α expression and anticancer composition containing the same |
US8765704B1 (en) | 2008-02-28 | 2014-07-01 | Novartis Ag | Modified small interfering RNA molecules and methods of use |
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US9309313B2 (en) | 2008-01-09 | 2016-04-12 | The Schepens Eye Research Institute, Inc. | Therapeutic compositions for treatment of ocular inflammatory disorders |
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US9999651B2 (en) | 2009-05-18 | 2018-06-19 | Sigmoid Pharma Limited | Composition comprising oil drops |
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Families Citing this family (130)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US9771586B2 (en) | 2002-11-14 | 2017-09-26 | Thermo Fisher Scientific Inc. | RNAi targeting ZNF205 |
US9719092B2 (en) | 2002-11-14 | 2017-08-01 | Thermo Fisher Scientific Inc. | RNAi targeting CNTD2 |
US9228186B2 (en) | 2002-11-14 | 2016-01-05 | Thermo Fisher Scientific Inc. | Methods and compositions for selecting siRNA of improved functionality |
US7951935B2 (en) | 2002-11-14 | 2011-05-31 | Dharmacon, Inc. | siRNA targeting v-myc myelocytomatosis viral oncogene homolog (MYC) |
US9719094B2 (en) | 2002-11-14 | 2017-08-01 | Thermo Fisher Scientific Inc. | RNAi targeting SEC61G |
US10011836B2 (en) | 2002-11-14 | 2018-07-03 | Thermo Fisher Scientific Inc. | Methods and compositions for selecting siRNA of improved functionality |
US9839649B2 (en) | 2002-11-14 | 2017-12-12 | Thermo Fisher Scientific Inc. | Methods and compositions for selecting siRNA of improved functionality |
EP2305813A3 (en) * | 2002-11-14 | 2012-03-28 | Dharmacon, Inc. | Fuctional and hyperfunctional sirna |
US8198427B1 (en) | 2002-11-14 | 2012-06-12 | Dharmacon, Inc. | SiRNA targeting catenin, beta-1 (CTNNB1) |
US7612196B2 (en) * | 2002-11-14 | 2009-11-03 | Dharmacon, Inc. | siRNA targeting cyclin-dependent kinase inhibitor 1B (p27, Kip1) (CDKN1B) |
US20100113307A1 (en) * | 2002-11-14 | 2010-05-06 | Dharmacon, Inc. | siRNA targeting vascular endothelial growth factor (VEGF) |
WO2006006948A2 (en) * | 2002-11-14 | 2006-01-19 | Dharmacon, Inc. | METHODS AND COMPOSITIONS FOR SELECTING siRNA OF IMPROVED FUNCTIONALITY |
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US20080268457A1 (en) * | 2002-11-14 | 2008-10-30 | Dharmacon, Inc. | siRNA targeting forkhead box P3 (FOXP3) |
US7592442B2 (en) * | 2002-11-14 | 2009-09-22 | Dharmacon, Inc. | siRNA targeting ribonucleotide reductase M2 polypeptide (RRM2 or RNR-R2) |
US9879266B2 (en) | 2002-11-14 | 2018-01-30 | Thermo Fisher Scientific Inc. | Methods and compositions for selecting siRNA of improved functionality |
US7691998B2 (en) * | 2002-11-14 | 2010-04-06 | Dharmacon, Inc. | siRNA targeting nucleoporin 62kDa (Nup62) |
US20090227780A1 (en) * | 2002-11-14 | 2009-09-10 | Dharmacon, Inc. | siRNA targeting connexin 43 |
US7635770B2 (en) * | 2002-11-14 | 2009-12-22 | Dharmacon, Inc. | siRNA targeting protein kinase N-3 (PKN-3) |
EP1620112A4 (en) * | 2003-04-17 | 2007-04-25 | Univ Columbia | Desmoglein 4 is a novel gene involved in hair growth |
US20070218551A1 (en) * | 2003-10-02 | 2007-09-20 | Chuan-Yuan Li | Novel Sirna-Based Approach to Target the Hif-Alpha Factor for Gene Therapy |
DE602004030369D1 (en) | 2003-10-24 | 2011-01-13 | Immunaid Pty Ltd | THERAPY PROCESS |
US7605250B2 (en) * | 2004-05-12 | 2009-10-20 | Dharmacon, Inc. | siRNA targeting cAMP-specific phosphodiesterase 4D |
IL162276A0 (en) * | 2004-06-01 | 2005-11-20 | Hadasit Med Res Service | Nucleic acid molecules as heparanase potent inhibitors, compositions and methods of use thereof |
WO2006023491A2 (en) | 2004-08-16 | 2006-03-02 | The Cbr Institute For Biomedical Research, Inc. | Method of delivering rna interference and uses thereof |
US7618947B2 (en) * | 2004-08-25 | 2009-11-17 | Isis Pharmaceuticals, Inc. | Modulation of HIF-1 beta expression |
US7718624B2 (en) * | 2004-09-01 | 2010-05-18 | Sitkovsky Michail V | Modulation of immune response and inflammation by targeting hypoxia inducible factors |
KR100780548B1 (en) | 2004-12-08 | 2007-11-29 | 한국원자력연구원 | - Small Interfering RNA Specific for S-adenosylmethionine Decarboxylase mRNA and Therapeutic Agent for Malignancy Comprising the Same |
US20100196509A1 (en) | 2005-02-28 | 2010-08-05 | Jonathan Braun | Methods for Diagnosis and Treatment of Endometrial Cancer |
US8318906B2 (en) | 2005-04-15 | 2012-11-27 | The Regents Of The University Of California | EMP2 antibodies and their therapeutic uses |
WO2006113526A2 (en) | 2005-04-15 | 2006-10-26 | The Regents Of The University Of California | Prevention of chlamydia infection using a protective antibody |
US8648052B2 (en) * | 2005-04-15 | 2014-02-11 | The Regents Of The University Of California | Prevention of chlamydia infection using SIRNA |
WO2007011819A2 (en) * | 2005-07-15 | 2007-01-25 | The Penn State Research Foundation | Ferritin as a therapeutic target in abnormal cells |
KR100749859B1 (en) * | 2005-10-18 | 2007-08-16 | 연세대학교 산학협력단 | Recombinant Adenovirus Expressing Specific with Enhanced Oncolytic Activity |
EP1976567B1 (en) | 2005-12-28 | 2020-05-13 | The Scripps Research Institute | Natural antisense and non-coding rna transcripts as drug targets |
US8673873B1 (en) * | 2005-12-28 | 2014-03-18 | Alcon Research, Ltd. | RNAi-mediated inhibition of phosphodiesterase type 4 for treatment of cAMP-related ocular disorders |
US20090130212A1 (en) * | 2006-05-15 | 2009-05-21 | Physical Pharmaceutica, Llc | Composition and improved method for preparation of small particles |
TW200808328A (en) * | 2006-06-02 | 2008-02-16 | Alcon Mfg Ltd | RNAi-mediated inhibition of stromal cell-derived factor 1-related targets for treatment of neovascularization-related conditions |
US20080152654A1 (en) * | 2006-06-12 | 2008-06-26 | Exegenics, Inc., D/B/A Opko Health, Inc. | COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS |
US7872118B2 (en) * | 2006-09-08 | 2011-01-18 | Opko Ophthalmics, Llc | siRNA and methods of manufacture |
WO2008070616A2 (en) * | 2006-12-01 | 2008-06-12 | University Of Utah Research Foundation | METHODS AND COMPOSITIONS RELATED TO HIF-1α |
US20090018094A1 (en) * | 2006-12-01 | 2009-01-15 | Loma Linda University Medical Center | Inhibition of brain enzymes involved in cerebral amyloid angiopathy and macular degeneration |
US20100055784A1 (en) * | 2007-03-02 | 2010-03-04 | Mdrna, Inc. | Nucleic acid compounds for inhibiting wnt gene expression and uses thereof |
EP2121923A1 (en) * | 2007-03-02 | 2009-11-25 | MDRNA, Inc. | Nucleic acid compounds for inhibiting erbb family gene expression and uses thereof |
WO2008109362A1 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting vegf gene expression and uses thereof |
EP2121925A2 (en) * | 2007-03-02 | 2009-11-25 | MDRNA, Inc. | Nucleic acid compounds for inhibiting ras gene expression and uses thereof |
US20080287383A1 (en) * | 2007-03-02 | 2008-11-20 | Nastech Pharmaceutical Company Inc. | Nucleic acid compounds for inhibiting erbb gene expression and uses thereof |
CA2679387A1 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting akt gene expression and uses thereof |
US20100011138A1 (en) * | 2008-07-09 | 2010-01-14 | International Business Machines Corporation | Design structure for automated means for determining internet access on a system on a chip |
DE102008035012A1 (en) | 2008-07-25 | 2010-02-04 | Fritz Egger Gmbh & Co. | Lightweight panel for furniture construction |
WO2010033248A2 (en) | 2008-09-22 | 2010-03-25 | Rxi Pharmaceuticals Corporation | Neutral nanotransporters |
US8153606B2 (en) | 2008-10-03 | 2012-04-10 | Opko Curna, Llc | Treatment of apolipoprotein-A1 related diseases by inhibition of natural antisense transcript to apolipoprotein-A1 |
EP2370582B1 (en) | 2008-12-04 | 2017-05-10 | CuRNA, Inc. | Treatment of tumor suppressor gene related diseases by inhibition of natural antisense transcript to the gene |
US8927511B2 (en) | 2008-12-04 | 2015-01-06 | Curna, Inc. | Treatment of vascular endothelial growth factor (VEGF) related diseases by inhibition of natural antisense transcript to VEGF |
ES2629630T3 (en) | 2008-12-04 | 2017-08-11 | Curna, Inc. | Treatment of diseases related to erythropoietin (EPO) by inhibiting the natural antisense transcript to EPO |
WO2010065834A1 (en) | 2008-12-04 | 2010-06-10 | Opko Ophthalmics, Llc | Compositions and methods for selective inhibition of pro-angiogenic vegf isoforms |
WO2010090762A1 (en) | 2009-02-04 | 2010-08-12 | Rxi Pharmaceuticals Corporation | Rna duplexes with single stranded phosphorothioate nucleotide regions for additional functionality |
ES2560107T3 (en) | 2009-02-12 | 2016-02-17 | Curna, Inc. | Treatment of diseases related to brain-derived neurotrophic factor (BDNF) by inhibition of natural antisense transcript for BDNF |
CA2755409C (en) | 2009-03-16 | 2019-04-30 | Joseph Collard | Treatment of nuclear factor (erythroid-derived 2)-like 2 (nrf2) related diseases by inhibition of natural antisense transcript to nrf2 |
JP5904935B2 (en) | 2009-03-17 | 2016-04-20 | クルナ・インコーポレーテッド | Treatment of DLK1-related diseases by suppression of natural antisense transcripts against Delta-like 1 homolog (DLK1) |
US20110045080A1 (en) * | 2009-03-24 | 2011-02-24 | William Marsh Rice University | Single-Walled Carbon Nanotube/Bioactive Substance Complexes and Methods Related Thereto |
US8283332B2 (en) * | 2009-04-17 | 2012-10-09 | University Of Louisville Research Foundation, Inc. | PFKFB4 inhibitors and methods of using the same |
CN102459596B (en) | 2009-05-06 | 2016-09-07 | 库尔纳公司 | By suppression therapy lipid transfer and the metabolic gene relevant disease of the natural antisense transcript for lipid transfer and metabolic gene |
KR101722541B1 (en) | 2009-05-06 | 2017-04-04 | 큐알엔에이, 인크. | Treatment of tristetraproline(ttp) related diseases by inhibition of natural antisense transcript to ttp |
CA2761248C (en) | 2009-05-08 | 2023-03-14 | Joseph Collard | Treatment of dystrophin family related diseases by inhibition of natural antisense transcript to dmd family |
ES2664590T3 (en) | 2009-05-18 | 2018-04-20 | Curna, Inc. | Treatment of diseases related to reprogramming factors by inhibition of the natural antisense transcript to a reprogramming factor |
US8895527B2 (en) | 2009-05-22 | 2014-11-25 | Curna, Inc. | Treatment of transcription factor E3 (TFE3) and insulin receptor substrate 2(IRS2) related diseases by inhibition of natural antisense transcript to TFE3 |
EP2982978A1 (en) | 2009-05-27 | 2016-02-10 | Immunaid Pty Ltd | Methods of treating diseases |
WO2010138806A2 (en) | 2009-05-28 | 2010-12-02 | Curna, Inc. | Treatment of antiviral gene related diseases by inhibition of natural antisense transcript to an antiviral gene |
JP5944311B2 (en) | 2009-06-16 | 2016-07-05 | クルナ・インコーポレーテッド | Treatment of collagen gene-related diseases by suppression of natural antisense transcripts against collagen genes |
US8951981B2 (en) | 2009-06-16 | 2015-02-10 | Curna, Inc. | Treatment of paraoxonase 1 (PON1) related diseases by inhibition of natural antisense transcript to PON1 |
JP6073133B2 (en) | 2009-06-24 | 2017-02-01 | クルナ・インコーポレーテッド | Treatment of TNFR2-related diseases by suppression of natural antisense transcripts against tumor necrosis factor receptor 2 (TNFR2) |
EP2446037B1 (en) | 2009-06-26 | 2016-04-20 | CuRNA, Inc. | Treatment of down syndrome gene related diseases by inhibition of natural antisense transcript to a down syndrome gene |
US20120252869A1 (en) | 2009-07-24 | 2012-10-04 | Opko Curna, Llc | Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) |
CN102762731B (en) | 2009-08-05 | 2018-06-22 | 库尔纳公司 | By inhibiting to treat insulin gene (INS) relevant disease for the natural antisense transcript of insulin gene (INS) |
CN104313027B (en) | 2009-08-11 | 2018-11-20 | 库尔纳公司 | By inhibiting the natural antisense transcript of adiponectin (ADIPOQ) to treat adiponectin (ADIPOQ) related disease |
KR101805213B1 (en) | 2009-08-21 | 2017-12-06 | 큐알엔에이, 인크. | Treatment of 'c terminus of hsp70-interacting protein' (chip) related diseases by inhibition of natural antisense transcript to chip |
WO2011031482A2 (en) | 2009-08-25 | 2011-03-17 | Curna, Inc. | Treatment of 'iq motif containing gtpase activating protein' (iqgap) related diseases by inhibition of natural antisense transcript to iqgap |
CN102791861B (en) | 2009-09-25 | 2018-08-07 | 库尔纳公司 | FLG relevant diseases are treated by adjusting expression and the activity of Filaggrin (FLG) |
US9799416B2 (en) * | 2009-11-06 | 2017-10-24 | Terrapower, Llc | Methods and systems for migrating fuel assemblies in a nuclear fission reactor |
AU2010321885B2 (en) | 2009-11-20 | 2015-12-24 | The Regents Of The University Of California | Epithelial membrane protein-2 (EMP2) and proliferative vitreoretinopathy (PVR) |
ES2661813T3 (en) | 2009-12-16 | 2018-04-04 | Curna, Inc. | Treatment of diseases related to membrane transcription factor peptidase, site 1 (mbtps1) by inhibition of the natural antisense transcript to the mbtps1 gene |
CA2782375C (en) | 2009-12-23 | 2023-10-31 | Opko Curna, Llc | Treatment of uncoupling protein 2 (ucp2) related diseases by inhibition of natural antisense transcript to ucp2 |
JP5934106B2 (en) | 2009-12-23 | 2016-06-15 | カッパーアールエヌエー,インコーポレイテッド | Treatment of HGF-related diseases by inhibition of natural antisense transcripts against hepatocyte growth factor (HGF) |
EP2519634B1 (en) | 2009-12-29 | 2016-06-01 | CuRNA, Inc. | TREATMENT OF TUMOR PROTEIN 63 (p63) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT TO p63 |
US8921334B2 (en) | 2009-12-29 | 2014-12-30 | Curna, Inc. | Treatment of nuclear respiratory factor 1 (NRF1) related diseases by inhibition of natural antisense transcript to NRF1 |
WO2011082281A2 (en) | 2009-12-31 | 2011-07-07 | Curna, Inc. | Treatment of insulin receptor substrate 2 (irs2) related diseases by inhibition of natural antisense transcript to irs2 and transcription factor e3 (tfe3) |
KR101878501B1 (en) | 2010-01-04 | 2018-08-07 | 큐알엔에이, 인크. | Treatment of interferon regulatory factor 8 (irf8) related diseases by inhibition of natural antisense transcript to irf8 |
KR101853509B1 (en) | 2010-01-06 | 2018-04-30 | 큐알엔에이, 인크. | Treatment of Pancreatic Developmental Gene Related Diseases By Inhibition of Natural Antisense Transcript to A Pancreatic Developmental Gene |
ES2664866T3 (en) | 2010-01-11 | 2018-04-23 | Curna, Inc. | Treatment of diseases related to sex hormone binding globulin (shbg) by inhibition of the natural antisense transcript to shbg |
CN102782135A (en) | 2010-01-25 | 2012-11-14 | 库尔纳公司 | Treatment of RNase H1 related diseases by inhibition of natural antisense transcript to RNase H1 |
US8962586B2 (en) | 2010-02-22 | 2015-02-24 | Curna, Inc. | Treatment of pyrroline-5-carboxylate reductase 1 (PYCR1) related diseases by inhibition of natural antisense transcript to PYCR1 |
EP2550000A4 (en) | 2010-03-24 | 2014-03-26 | Advirna Inc | Reduced size self-delivering rnai compounds |
WO2011119871A1 (en) | 2010-03-24 | 2011-09-29 | Rxi Phrmaceuticals Corporation | Rna interference in ocular indications |
KR101877065B1 (en) | 2010-04-02 | 2018-07-10 | 큐알엔에이, 인크. | Treatment of colony-stimulating factor 3 (csf3) related diseases by inhibition of natural antisense transcript to csf3 |
CN102858979B (en) | 2010-04-09 | 2018-01-26 | 库尔纳公司 | FGF21 relevant diseases are treated by suppressing the natural antisense transcript of FGF2 1 (FGF21) |
WO2011139387A1 (en) | 2010-05-03 | 2011-11-10 | Opko Curna, Llc | Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) |
TWI586356B (en) | 2010-05-14 | 2017-06-11 | 可娜公司 | Treatment of par4 related diseases by inhibition of natural antisense transcript to par4 |
RU2620978C2 (en) | 2010-05-26 | 2017-05-30 | Курна, Инк. | Treatment of diseases associated with methionine sulfoxide reductase a (msra), by msra natural antisense transcript inhibition |
NO2576783T3 (en) | 2010-05-26 | 2018-04-28 | ||
JP6023705B2 (en) | 2010-06-23 | 2016-11-09 | カッパーアールエヌエー,インコーポレイテッド | Treatment of SCNA-related diseases by inhibition of natural antisense transcripts on sodium channels, voltage-gated, alpha subunit (SCNA) |
US8980860B2 (en) | 2010-07-14 | 2015-03-17 | Curna, Inc. | Treatment of discs large homolog (DLG) related diseases by inhibition of natural antisense transcript to DLG |
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US10000752B2 (en) | 2010-11-18 | 2018-06-19 | Curna, Inc. | Antagonat compositions and methods of use |
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CN103328038A (en) | 2010-12-01 | 2013-09-25 | 史拜诺莫度雷森公司 | Directed delivery of agents to neural anatomy |
WO2012100172A2 (en) | 2011-01-22 | 2012-07-26 | Dicerna Pharmaceuticals, Inc. | Methods and compositions for the specific inhibition of hif-1a by double stranded rna |
SG193923A1 (en) * | 2011-03-29 | 2013-11-29 | Alnylam Pharmaceuticals Inc | Compositions and methods for inhibiting expression of tmprss6 gene |
JP6188686B2 (en) | 2011-06-09 | 2017-08-30 | カッパーアールエヌエー,インコーポレイテッド | Treatment of FXN-related diseases by inhibition of natural antisense transcripts to frataxin (FXN) |
KR101337767B1 (en) * | 2011-07-26 | 2013-12-09 | 서울대학교산학협력단 | New peptides to increase VEGF expression and a pharmaceutical composition comprising the same |
CN108272782B (en) | 2011-09-06 | 2021-04-23 | 库尔纳公司 | Use of small molecules in preparation of medicine for treating Dravet syndrome or generalized epilepsy with febrile convulsion adjunctive disease |
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BR112023022284A2 (en) | 2021-04-26 | 2023-12-26 | Alnylam Pharmaceuticals Inc | COMPOSITIONS OF TRANSMEMBRANE PROTEASE IRNA, SERINE 6 (TMPRSS6) AND METHODS OF USE THEREOF |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993024641A2 (en) | 1992-06-02 | 1993-12-09 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Adeno-associated virus with inverted terminal repeat sequences as promoter |
WO1994013788A1 (en) | 1992-12-04 | 1994-06-23 | University Of Pittsburgh | Recombinant viral vector system |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6177401B1 (en) * | 1992-11-13 | 2001-01-23 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften | Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis |
US5731294A (en) * | 1993-07-27 | 1998-03-24 | Hybridon, Inc. | Inhibition of neovasularization using VEGF-specific oligonucleotides |
US5624803A (en) * | 1993-10-14 | 1997-04-29 | The Regents Of The University Of California | In vivo oligonucleotide generator, and methods of testing the binding affinity of triplex forming oligonucleotides derived therefrom |
US5882914A (en) * | 1995-06-06 | 1999-03-16 | The Johns Hopkins University School Of Medicine | Nucleic acids encoding the hypoxia inducible factor-1 |
US6506559B1 (en) * | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
DE19956568A1 (en) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Method and medicament for inhibiting the expression of a given gene |
JP2003526367A (en) | 2000-03-16 | 2003-09-09 | ジェネティカ インコーポレイテッド | RNA interference method and RNA interference composition |
PT1309726E (en) | 2000-03-30 | 2010-03-08 | Whitehead Biomedical Inst | Rna sequence-specific mediators of rna interference |
US20020132788A1 (en) | 2000-11-06 | 2002-09-19 | David Lewis | Inhibition of gene expression by delivery of small interfering RNA to post-embryonic animal cells in vivo |
US20020173478A1 (en) | 2000-11-14 | 2002-11-21 | The Trustees Of The University Of Pennsylvania | Post-transcriptional gene silencing by RNAi in mammalian cells |
DK2813582T3 (en) * | 2000-12-01 | 2017-07-31 | Max-Planck-Gesellschaft Zur Förderung Der Wss E V | Small RNA molecules that mediate RNA interference |
JP4590157B2 (en) | 2001-03-21 | 2010-12-01 | アイシス イノヴェイション リミテッド | Assays, methods and means |
EP1461333A1 (en) | 2001-11-22 | 2004-09-29 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
JP4338527B2 (en) | 2002-04-05 | 2009-10-07 | サンタリス ファーマ アー/エス | Oligomer compounds that regulate HIF-1α expression |
KR20120038546A (en) | 2002-11-01 | 2012-04-23 | 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 | Compositions and methods for sirna inhibition of hif-1 alpha |
-
2003
- 2003-10-31 KR KR1020127005480A patent/KR20120038546A/en not_active Application Discontinuation
- 2003-10-31 WO PCT/US2003/034826 patent/WO2004042024A2/en active Application Filing
- 2003-10-31 JP JP2004550399A patent/JP5449639B2/en not_active Expired - Fee Related
- 2003-10-31 KR KR1020057007448A patent/KR20050083855A/en active IP Right Grant
- 2003-10-31 NZ NZ540779A patent/NZ540779A/en not_active IP Right Cessation
- 2003-10-31 EP EP03768569A patent/EP1562970A4/en not_active Withdrawn
- 2003-10-31 CA CA2504926A patent/CA2504926C/en not_active Expired - Fee Related
- 2003-10-31 AU AU2003291678A patent/AU2003291678B2/en not_active Ceased
- 2003-10-31 US US10/699,557 patent/US7521431B2/en not_active Expired - Fee Related
- 2003-10-31 MX MXPA05004722A patent/MXPA05004722A/en active IP Right Grant
-
2005
- 2005-04-25 IL IL168224A patent/IL168224A/en not_active IP Right Cessation
-
2009
- 2009-01-26 US US12/359,505 patent/US7645744B2/en not_active Expired - Fee Related
- 2009-12-03 US US12/630,077 patent/US8236775B2/en not_active Expired - Fee Related
-
2010
- 2010-09-27 JP JP2010216077A patent/JP2011057677A/en active Pending
-
2012
- 2012-07-23 US US13/555,589 patent/US20120308645A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993024641A2 (en) | 1992-06-02 | 1993-12-09 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Adeno-associated virus with inverted terminal repeat sequences as promoter |
WO1994013788A1 (en) | 1992-12-04 | 1994-06-23 | University Of Pittsburgh | Recombinant viral vector system |
Non-Patent Citations (1)
Title |
---|
See also references of EP1562970A4 |
Cited By (106)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8318689B2 (en) | 2001-11-09 | 2012-11-27 | Centre National De La Recherche Scientifique | SiRNA-based cancer treatment |
US8785617B2 (en) | 2002-04-05 | 2014-07-22 | Santaris Pharma A/S | Oligomeric compounds for the modulation of HIF-1A expression |
US8357670B2 (en) | 2002-04-05 | 2013-01-22 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation of HIF-1A expression |
US7846911B2 (en) | 2002-04-05 | 2010-12-07 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation of HIF-1alpha expression |
US7737264B2 (en) | 2002-04-05 | 2010-06-15 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation HIF-1α expression |
US8207140B2 (en) | 2002-04-05 | 2012-06-26 | Santaris Pharma A/S | Oligomeric compounds for the modulation of HIF-1α expression |
US8236775B2 (en) | 2002-11-01 | 2012-08-07 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of HIF-1 α |
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US8513400B2 (en) | 2002-11-23 | 2013-08-20 | Isis Pharmaceuticals, Inc. | Modulation of HIF1α and HIF2α expression |
EP2363503A1 (en) * | 2002-11-23 | 2011-09-07 | ISIS Pharmaceuticals, Inc. | Modulation of HIF1A and HIF2A expression |
WO2005035759A2 (en) * | 2003-08-20 | 2005-04-21 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HYPOXIA INDUCIBLE FACTOR 1 (HIF1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2005035759A3 (en) * | 2003-08-20 | 2006-03-16 | Nassim Usman | RNA INTERFERENCE MEDIATED INHIBITION OF HYPOXIA INDUCIBLE FACTOR 1 (HIF1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US8642571B2 (en) | 2004-08-06 | 2014-02-04 | Quark Pharmaceuticals, Inc. | Therapeutic uses of inhibitors of RTP801 |
US8168607B2 (en) | 2004-08-06 | 2012-05-01 | Quark Pharmaceuticals Inc. | Methods of treating eye diseases in diabetic patients |
US7741299B2 (en) * | 2004-08-16 | 2010-06-22 | Quark Pharmaceuticals, Inc. | Therapeutic uses of inhibitors of RTP801 |
US8309532B2 (en) | 2004-08-16 | 2012-11-13 | Quark Pharmaceuticals, Inc. | Therapeutic uses of inhibitors of RTP801 |
US8258110B2 (en) | 2004-08-23 | 2012-09-04 | Sylentis S.A.U. | Methods and compositions for the treatment of eye disorders with increased intraocular pressure |
US8198250B2 (en) | 2004-08-23 | 2012-06-12 | Sylentis S.A.U. | Methods and compositions for the treatment of eye disorders with increased intraocular pressure |
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US7902169B2 (en) | 2004-08-23 | 2011-03-08 | Sylentis S.A.U. | Methods and compositions for the treatment of eye disorders with increased intraocular pressure |
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US8252758B2 (en) | 2004-08-23 | 2012-08-28 | Sylentis S.A.U. | Methods and compositions for the treatment of eye disorders with increased intraocular pressure |
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US8247387B2 (en) | 2004-08-23 | 2012-08-21 | Sylentis S.A.U. | Methods and compositions for the treatment of eye disorders with increased intraocular pressure |
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US7939507B2 (en) | 2004-11-09 | 2011-05-10 | Enzon Pharmaceuticals, Inc. | Potent LNA oligonucleotides for the inhibition of HIF-1a expression |
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US7589190B2 (en) | 2004-11-09 | 2009-09-15 | Enzon Pharmaceuticals, Inc. | Potent LNA oligonucleotides for the inhibition of HIF-1A expression |
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WO2006083945A2 (en) * | 2005-02-01 | 2006-08-10 | Alcon, Inc. | Rnai-mediated inhibition of ocular targets |
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US7872119B2 (en) | 2007-02-26 | 2011-01-18 | Quark Pharmaceuticals, Inc. | Inhibitors of RTP801 and their use in disease treatment |
WO2008109381A2 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting hif1a gene expression and uses thereof |
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Also Published As
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US8236775B2 (en) | 2012-08-07 |
MXPA05004722A (en) | 2005-08-03 |
KR20050083855A (en) | 2005-08-26 |
WO2004042024B1 (en) | 2004-11-11 |
EP1562970A2 (en) | 2005-08-17 |
US20100136101A1 (en) | 2010-06-03 |
EP1562970A4 (en) | 2006-04-12 |
US20090191263A1 (en) | 2009-07-30 |
AU2003291678B2 (en) | 2009-01-15 |
CA2504926A1 (en) | 2004-05-21 |
NZ540779A (en) | 2008-05-30 |
IL168224A (en) | 2010-12-30 |
CA2504926C (en) | 2014-01-14 |
JP2006504433A (en) | 2006-02-09 |
US7645744B2 (en) | 2010-01-12 |
WO2004042024A3 (en) | 2004-09-23 |
AU2003291678A1 (en) | 2004-06-07 |
US20040180357A1 (en) | 2004-09-16 |
JP2011057677A (en) | 2011-03-24 |
KR20120038546A (en) | 2012-04-23 |
US7521431B2 (en) | 2009-04-21 |
JP5449639B2 (en) | 2014-03-19 |
US20120308645A1 (en) | 2012-12-06 |
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