MX2020011006A - Pcsk9 dirigido a oligonucleótidos para el tratamiento de la hipercolesterolemia y afecciones relacionadas. - Google Patents
Pcsk9 dirigido a oligonucleótidos para el tratamiento de la hipercolesterolemia y afecciones relacionadas.Info
- Publication number
- MX2020011006A MX2020011006A MX2020011006A MX2020011006A MX2020011006A MX 2020011006 A MX2020011006 A MX 2020011006A MX 2020011006 A MX2020011006 A MX 2020011006A MX 2020011006 A MX2020011006 A MX 2020011006A MX 2020011006 A MX2020011006 A MX 2020011006A
- Authority
- MX
- Mexico
- Prior art keywords
- oligonucleotides
- related conditions
- treating hypercholesterolemia
- targeting oligonucleotides
- pcsk9 expression
- Prior art date
Links
- 108091034117 Oligonucleotide Proteins 0.000 title abstract 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 title abstract 4
- 208000035150 Hypercholesterolemia Diseases 0.000 title abstract 2
- 230000008685 targeting Effects 0.000 title abstract 2
- 101150094724 PCSK9 gene Proteins 0.000 title 1
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 abstract 3
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 abstract 3
- 210000003494 hepatocyte Anatomy 0.000 abstract 2
- 201000001320 Atherosclerosis Diseases 0.000 abstract 1
- 101710163270 Nuclease Proteins 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 abstract 1
- 230000005847 immunogenicity Effects 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 210000004185 liver Anatomy 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 210000000056 organ Anatomy 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21061—Kexin (3.4.21.61), i.e. proprotein convertase subtilisin/kexin type 9
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/322—2'-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
- C12N2310/533—Physical structure partially self-complementary or closed having a mismatch or nick in at least one of the strands
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862659693P | 2018-04-18 | 2018-04-18 | |
| US201962820558P | 2019-03-19 | 2019-03-19 | |
| PCT/US2019/025253 WO2019204021A1 (en) | 2018-04-18 | 2019-04-01 | Pcsk9 targeting oligonucleotides for treating hypercholesterolemia and related conditions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2020011006A true MX2020011006A (es) | 2021-01-20 |
Family
ID=68239855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2020011006A MX2020011006A (es) | 2018-04-18 | 2019-04-01 | Pcsk9 dirigido a oligonucleótidos para el tratamiento de la hipercolesterolemia y afecciones relacionadas. |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US11566248B2 (OSRAM) |
| EP (1) | EP3765611A4 (OSRAM) |
| JP (2) | JP7357002B2 (OSRAM) |
| KR (1) | KR102749200B1 (OSRAM) |
| CN (1) | CN112368381A (OSRAM) |
| AU (1) | AU2019255460A1 (OSRAM) |
| CA (1) | CA3097585A1 (OSRAM) |
| IL (1) | IL278086A (OSRAM) |
| MX (1) | MX2020011006A (OSRAM) |
| WO (1) | WO2019204021A1 (OSRAM) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019006455A1 (en) | 2017-06-30 | 2019-01-03 | Solstice Biologics, Ltd. | AUXILIARIES OF CHIRAL PHOSPHORAMIDITIS AND METHODS OF USE THEREOF |
| MX2020011006A (es) * | 2018-04-18 | 2021-01-20 | Dicerna Pharmaceuticals Inc | Pcsk9 dirigido a oligonucleótidos para el tratamiento de la hipercolesterolemia y afecciones relacionadas. |
| AU2020268798A1 (en) | 2019-05-03 | 2021-11-04 | Dicerna Pharmaceuticals, Inc. | Double-stranded nucleic acid inhibitor molecules with shortened sense strands |
| WO2021037972A1 (en) * | 2019-08-27 | 2021-03-04 | Sanofi | Compositions and methods for inhibiting pcsk9 |
| WO2022089486A1 (zh) * | 2020-10-28 | 2022-05-05 | 江苏柯菲平医药股份有限公司 | 抑制PCSK9基因表达的siRNA及其修饰物与应用 |
| CN114634929A (zh) * | 2020-12-16 | 2022-06-17 | 施能康生物科技有限公司 | 靶向前蛋白转化酶枯草杆菌转化酶的核酸及其用途 |
| WO2023017004A1 (en) * | 2021-08-09 | 2023-02-16 | Cargene Therapeutics Pte. Ltd. | Inhibitory nucleic acids for pcsk9 |
| WO2023051822A1 (zh) * | 2021-09-30 | 2023-04-06 | 北京安龙生物医药有限公司 | 用于治疗与pcsk9相关疾病的靶向寡核苷酸 |
| EP4464781A1 (en) * | 2022-01-13 | 2024-11-20 | CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Rnai agent inhibiting pcsk9 gene expression and application thereof |
| JP2025520520A (ja) * | 2022-06-14 | 2025-07-03 | 大睿生物 | ＰＣＳＫ９遺伝子活性を調節するｓｉＲＮＡ分子 |
| CN118086311B (zh) * | 2023-05-25 | 2024-08-09 | 苏州时安生物技术有限公司 | 抑制PCSK9基因表达的siRNA、其缀合物和药物组合物及用途 |
| EP4731764A2 (en) * | 2023-06-21 | 2026-04-29 | Sanegene Bio USA Inc. | Double stranded rna targeting proprotein convertase subtilisin kexin 9 (pcsk9) and methods of use thereof |
| CN121006363A (zh) * | 2023-09-18 | 2025-11-25 | 广州必贝特医药股份有限公司 | 用于同时抑制两个靶基因表达的siRNA、药物及其应用 |
| CN117106781B (zh) * | 2023-10-16 | 2024-03-22 | 深圳市茵冠生物科技有限公司 | 修饰的核酸及其产品和应用 |
| WO2025096355A1 (en) * | 2023-10-29 | 2025-05-08 | Corsera Llc | Improved sirna for silencing expression of pcsk9 and uses thereof |
| CN117210468B (zh) * | 2023-11-06 | 2024-02-20 | 北京悦康科创医药科技股份有限公司 | 靶向调控PCSK9基因表达的siRNA及其应用 |
| CN117384907B (zh) * | 2023-12-11 | 2024-03-29 | 上海鼎新基因科技有限公司 | 抑制PCSK9表达的siRNA分子及其应用 |
| CN118109463B (zh) * | 2024-01-31 | 2025-02-21 | 北京悦康科创医药科技股份有限公司 | 靶向PCSK9基因的siRNA及其应用 |
| WO2026026812A1 (zh) * | 2024-07-29 | 2026-02-05 | 成都先衍生物技术有限公司 | 一种具有双靶点基因抑制作用的核酸缀合物及其应用 |
| WO2026026811A1 (zh) * | 2024-07-29 | 2026-02-05 | 成都先衍生物技术有限公司 | 一种具有双靶点基因抑制作用的核酸缀合物及其应用 |
| WO2026092650A1 (zh) * | 2024-11-01 | 2026-05-07 | 迈威(上海)生物科技股份有限公司 | 一种抑制LPA基因表达的RNAi制剂及其应用 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484588B (zh) | 2006-05-11 | 2013-11-06 | 阿尔尼拉姆医药品有限公司 | 抑制pcsk9基因表达的组合物和方法 |
| CA2658183A1 (en) | 2006-07-17 | 2008-01-24 | Sirna Therapeutics Inc. | Rna interference mediated inhibition of proprotein convertase subtilisin kexin 9 (pcsk9) gene expression using short interfering nucleic acid (sina) |
| EP2455471A3 (en) | 2006-11-27 | 2012-09-12 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
| WO2008109369A2 (en) | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting tnf gene expression and uses thereof |
| WO2009114475A2 (en) | 2008-03-09 | 2009-09-17 | Intradigm Corporation | Compositions comprising human pcsk9 and apolipoprotein b sirna and methods of use |
| US9493774B2 (en) | 2009-01-05 | 2016-11-15 | Rxi Pharmaceuticals Corporation | Inhibition of PCSK9 through RNAi |
| AU2010260148A1 (en) * | 2009-06-15 | 2012-02-02 | Alnylam Pharmaceuticals, Inc. | Lipid formulated dsRNA targeting the PCSK9 gene |
| CA2816321A1 (en) | 2010-10-29 | 2012-05-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibition of pcsk9 genes |
| ES2747842T3 (es) * | 2014-12-15 | 2020-03-11 | Dicerna Pharmaceuticals Inc | Acidos nucleicos de doble hebra modificados por ligando |
| MX2020011006A (es) | 2018-04-18 | 2021-01-20 | Dicerna Pharmaceuticals Inc | Pcsk9 dirigido a oligonucleótidos para el tratamiento de la hipercolesterolemia y afecciones relacionadas. |
-
2019
- 2019-04-01 MX MX2020011006A patent/MX2020011006A/es unknown
- 2019-04-01 CN CN201980041119.4A patent/CN112368381A/zh not_active Withdrawn
- 2019-04-01 JP JP2020557924A patent/JP7357002B2/ja active Active
- 2019-04-01 US US17/048,846 patent/US11566248B2/en active Active
- 2019-04-01 KR KR1020207032782A patent/KR102749200B1/ko active Active
- 2019-04-01 EP EP19787636.0A patent/EP3765611A4/en not_active Withdrawn
- 2019-04-01 AU AU2019255460A patent/AU2019255460A1/en not_active Withdrawn
- 2019-04-01 WO PCT/US2019/025253 patent/WO2019204021A1/en not_active Ceased
- 2019-04-01 CA CA3097585A patent/CA3097585A1/en active Pending
-
2020
- 2020-10-15 IL IL278086A patent/IL278086A/en unknown
-
2022
- 2022-11-30 US US18/060,406 patent/US20230250435A1/en not_active Abandoned
-
2023
- 2023-09-25 JP JP2023159941A patent/JP2023174697A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| KR102749200B1 (ko) | 2025-01-03 |
| CA3097585A1 (en) | 2019-10-24 |
| JP2021521796A (ja) | 2021-08-30 |
| US11566248B2 (en) | 2023-01-31 |
| US20210238606A1 (en) | 2021-08-05 |
| KR20210005068A (ko) | 2021-01-13 |
| EP3765611A1 (en) | 2021-01-20 |
| EP3765611A4 (en) | 2022-05-04 |
| JP7357002B2 (ja) | 2023-10-05 |
| WO2019204021A1 (en) | 2019-10-24 |
| US20230250435A1 (en) | 2023-08-10 |
| CN112368381A (zh) | 2021-02-12 |
| AU2019255460A1 (en) | 2020-11-12 |
| JP2023174697A (ja) | 2023-12-08 |
| IL278086A (en) | 2020-11-30 |
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