JP6991966B2 - Ｌｐａの遺伝子発現の阻害のための組成物及び方法 - Google Patents
Ｌｐａの遺伝子発現の阻害のための組成物及び方法 Download PDFInfo
- Publication number
- JP6991966B2 JP6991966B2 JP2018516738A JP2018516738A JP6991966B2 JP 6991966 B2 JP6991966 B2 JP 6991966B2 JP 2018516738 A JP2018516738 A JP 2018516738A JP 2018516738 A JP2018516738 A JP 2018516738A JP 6991966 B2 JP6991966 B2 JP 6991966B2
- Authority
- JP
- Japan
- Prior art keywords
- rnai agent
- seq
- lpa
- lpa rnai
- sequence
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000014509 gene expression Effects 0.000 title claims description 42
- 101150091521 lpa gene Proteins 0.000 title claims description 14
- 230000005764 inhibitory process Effects 0.000 title claims description 8
- 238000000034 method Methods 0.000 title description 27
- 239000000203 mixture Substances 0.000 title description 15
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 claims description 398
- 230000009368 gene silencing by RNA Effects 0.000 claims description 398
- 108010033266 Lipoprotein(a) Proteins 0.000 claims description 368
- 239000003795 chemical substances by application Substances 0.000 claims description 355
- 125000003729 nucleotide group Chemical group 0.000 claims description 278
- 239000002773 nucleotide Substances 0.000 claims description 224
- 230000000692 anti-sense effect Effects 0.000 claims description 176
- 108091081021 Sense strand Proteins 0.000 claims description 138
- 230000000295 complement effect Effects 0.000 claims description 38
- 150000002256 galaktoses Chemical class 0.000 claims description 28
- 210000002966 serum Anatomy 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 239000002777 nucleoside Substances 0.000 claims description 21
- -1 phosphorothioate nucleoside Chemical class 0.000 claims description 20
- 239000003446 ligand Substances 0.000 claims description 18
- BXJSAMKIFDDLGI-UHFFFAOYSA-N 2-(dimethylamino)-N-[2-[3-[[5-[3-(dimethylcarbamoyl)phenyl]-2-methoxyphenyl]sulfonylamino]anilino]ethyl]benzamide Chemical compound COc1ccc(cc1S(=O)(=O)Nc1cccc(NCCNC(=O)c2ccccc2N(C)C)c1)-c1cccc(c1)C(=O)N(C)C BXJSAMKIFDDLGI-UHFFFAOYSA-N 0.000 claims description 17
- 229930182830 galactose Natural products 0.000 claims description 17
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 claims description 13
- 108010006523 asialoglycoprotein receptor Proteins 0.000 claims description 13
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims description 12
- 101001024442 Cellulomonas fimi Beta-N-acetylglucosaminidase/beta-glucosidase Proteins 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 3
- 125000001921 locked nucleotide group Chemical group 0.000 claims description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 101100239890 Candida albicans (strain SC5314 / ATCC MYA-2876) NAG4 gene Proteins 0.000 claims 1
- 230000003278 mimic effect Effects 0.000 claims 1
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 372
- 238000012384 transportation and delivery Methods 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 51
- 229920000642 polymer Polymers 0.000 description 49
- 238000003197 gene knockdown Methods 0.000 description 38
- 125000005647 linker group Chemical group 0.000 description 38
- 241000699670 Mus sp. Species 0.000 description 36
- 101710115418 Apolipoprotein(a) Proteins 0.000 description 34
- 101710119581 Melittin-like peptide Proteins 0.000 description 28
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 24
- 210000001519 tissue Anatomy 0.000 description 23
- 108020004999 messenger RNA Proteins 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000001990 intravenous administration Methods 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 19
- 239000003814 drug Substances 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 239000007924 injection Substances 0.000 description 16
- 238000002347 injection Methods 0.000 description 16
- 125000006850 spacer group Chemical group 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 238000001727 in vivo Methods 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 238000007920 subcutaneous administration Methods 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 14
- 229940124597 therapeutic agent Drugs 0.000 description 14
- 108091028043 Nucleic acid sequence Proteins 0.000 description 13
- 230000000875 corresponding effect Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 150000002632 lipids Chemical group 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 11
- 150000003833 nucleoside derivatives Chemical class 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 241000282567 Macaca fascicularis Species 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 208000026106 cerebrovascular disease Diseases 0.000 description 9
- 210000003494 hepatocyte Anatomy 0.000 description 9
- 108091033319 polynucleotide Proteins 0.000 description 9
- 102000040430 polynucleotide Human genes 0.000 description 9
- 239000002157 polynucleotide Substances 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 8
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 150000007523 nucleic acids Chemical class 0.000 description 8
- 239000013612 plasmid Substances 0.000 description 8
- 238000011830 transgenic mouse model Methods 0.000 description 8
- 101000889990 Homo sapiens Apolipoprotein(a) Proteins 0.000 description 7
- 230000003143 atherosclerotic effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- 241000288906 Primates Species 0.000 description 6
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 206010002388 Angina unstable Diseases 0.000 description 5
- 206010002915 Aortic valve incompetence Diseases 0.000 description 5
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 5
- 208000002251 Dissecting Aneurysm Diseases 0.000 description 5
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 5
- 206010021263 IgA nephropathy Diseases 0.000 description 5
- 102000007330 LDL Lipoproteins Human genes 0.000 description 5
- 108010007622 LDL Lipoproteins Proteins 0.000 description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 5
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 5
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 5
- 206010038378 Renal artery stenosis Diseases 0.000 description 5
- 208000007718 Stable Angina Diseases 0.000 description 5
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 5
- 208000007814 Unstable Angina Diseases 0.000 description 5
- 206010047249 Venous thrombosis Diseases 0.000 description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 206010002895 aortic dissection Diseases 0.000 description 5
- 201000002064 aortic valve insufficiency Diseases 0.000 description 5
- 208000029078 coronary artery disease Diseases 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 5
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 210000001363 mesenteric artery superior Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000013638 trimer Substances 0.000 description 5
- 108010071619 Apolipoproteins Proteins 0.000 description 4
- 102000007592 Apolipoproteins Human genes 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 206010022680 Intestinal ischaemia Diseases 0.000 description 4
- 235000000421 Lepidium meyenii Nutrition 0.000 description 4
- 240000000759 Lepidium meyenii Species 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 208000004535 Mesenteric Ischemia Diseases 0.000 description 4
- 108010052090 Renilla Luciferases Proteins 0.000 description 4
- 201000007527 Retinal artery occlusion Diseases 0.000 description 4
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000012750 in vivo screening Methods 0.000 description 4
- 235000012902 lepidium meyenii Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000000693 micelle Substances 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 229930024421 Adenine Natural products 0.000 description 3
- 208000003017 Aortic Valve Stenosis Diseases 0.000 description 3
- 108010012927 Apoprotein(a) Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 description 3
- 102000004895 Lipoproteins Human genes 0.000 description 3
- 108090001030 Lipoproteins Proteins 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- 206010002906 aortic stenosis Diseases 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 239000005547 deoxyribonucleotide Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 150000008300 phosphoramidites Chemical class 0.000 description 3
- 238000002203 pretreatment Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229940126586 small molecule drug Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 2
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 description 2
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7-deaza-adenine Chemical compound NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 description 2
- HCGHYQLFMPXSDU-UHFFFAOYSA-N 7-methyladenine Chemical compound C1=NC(N)=C2N(C)C=NC2=N1 HCGHYQLFMPXSDU-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 102100025668 Angiopoietin-related protein 3 Human genes 0.000 description 2
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 2
- 102100030970 Apolipoprotein C-III Human genes 0.000 description 2
- 108010002913 Asialoglycoproteins Proteins 0.000 description 2
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 2
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 2
- 101500014077 Bombina orientalis C-terminal extension peptide Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 101000693085 Homo sapiens Angiopoietin-related protein 3 Proteins 0.000 description 2
- 101000793223 Homo sapiens Apolipoprotein C-III Proteins 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N Hypoxanthine Natural products O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- 108010036176 Melitten Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 101000930477 Mus musculus Albumin Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- 229940127355 PCSK9 Inhibitors Drugs 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000003838 adenosines Chemical class 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- 238000000137 annealing Methods 0.000 description 2
- 210000001765 aortic valve Anatomy 0.000 description 2
- 239000002214 arabinonucleotide Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- GOHCTCOGYKAJLZ-UHFFFAOYSA-N ctep Chemical compound CC=1N(C=2C=CC(OC(F)(F)F)=CC=2)C(C)=NC=1C#CC1=CC=NC(Cl)=C1 GOHCTCOGYKAJLZ-UHFFFAOYSA-N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- FBWJHGIUUCOZRM-UHFFFAOYSA-N cyclopropylphosphonic acid Chemical compound OP(O)(=O)C1CC1 FBWJHGIUUCOZRM-UHFFFAOYSA-N 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 2
- 230000012202 endocytosis Effects 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 229960000815 ezetimibe Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 102000045903 human LPA Human genes 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- OVHQWOXKMOVDJP-UHFFFAOYSA-N melitin Chemical compound OC1C(O)C(O)C(C)OC1OC1C(O)C(OC=2C=C3C(C(C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)C(CO)O5)O)O4)O)=C(C=4C=CC(O)=CC=4)O3)=O)=C(O)C=2)OC(C)C1O OVHQWOXKMOVDJP-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 229940071643 prefilled syringe Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 238000010223 real-time analysis Methods 0.000 description 2
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical group OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 210000003752 saphenous vein Anatomy 0.000 description 2
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- AVBGNFCMKJOFIN-UHFFFAOYSA-N triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- YIMATHOGWXZHFX-WCTZXXKLSA-N (2r,3r,4r,5r)-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolane-2,4-diol Chemical compound COCCO[C@H]1[C@H](O)O[C@H](CO)[C@H]1O YIMATHOGWXZHFX-WCTZXXKLSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical class C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- UHUHBFMZVCOEOV-UHFFFAOYSA-N 1h-imidazo[4,5-c]pyridin-4-amine Chemical compound NC1=NC=CC2=C1N=CN2 UHUHBFMZVCOEOV-UHFFFAOYSA-N 0.000 description 1
- QSHACTSJHMKXTE-UHFFFAOYSA-N 2-(2-aminopropyl)-7h-purin-6-amine Chemical compound CC(N)CC1=NC(N)=C2NC=NC2=N1 QSHACTSJHMKXTE-UHFFFAOYSA-N 0.000 description 1
- NCYUNOARGQPCSH-UHFFFAOYSA-N 2-(2-ethoxyethylamino)prop-2-enoic acid Chemical compound CCOCCNC(=C)C(=O)O NCYUNOARGQPCSH-UHFFFAOYSA-N 0.000 description 1
- KXTUJUVCAGXOBN-WQXQQRIOSA-N 2-methyl-N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CC(C)C(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O KXTUJUVCAGXOBN-WQXQQRIOSA-N 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- GXGKKIPUFAHZIZ-UHFFFAOYSA-N 5-benzylsulfanyl-2h-tetrazole Chemical compound C=1C=CC=CC=1CSC=1N=NNN=1 GXGKKIPUFAHZIZ-UHFFFAOYSA-N 0.000 description 1
- ZLAQATDNGLKIEV-UHFFFAOYSA-N 5-methyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound CC1=CNC(=S)NC1=O ZLAQATDNGLKIEV-UHFFFAOYSA-N 0.000 description 1
- LKDWQHQNDDNHSC-UHFFFAOYSA-N 5-phenyl-1,2,4-dithiazol-3-one Chemical compound S1SC(=O)N=C1C1=CC=CC=C1 LKDWQHQNDDNHSC-UHFFFAOYSA-N 0.000 description 1
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- LOSIULRWFAEMFL-UHFFFAOYSA-N 7-deazaguanine Chemical compound O=C1NC(N)=NC2=C1CC=N2 LOSIULRWFAEMFL-UHFFFAOYSA-N 0.000 description 1
- HRYKDUPGBWLLHO-UHFFFAOYSA-N 8-azaadenine Chemical compound NC1=NC=NC2=NNN=C12 HRYKDUPGBWLLHO-UHFFFAOYSA-N 0.000 description 1
- LPXQRXLUHJKZIE-UHFFFAOYSA-N 8-azaguanine Chemical compound NC1=NC(O)=C2NN=NC2=N1 LPXQRXLUHJKZIE-UHFFFAOYSA-N 0.000 description 1
- 229960005508 8-azaguanine Drugs 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101710095342 Apolipoprotein B Proteins 0.000 description 1
- 108010008150 Apolipoprotein B-100 Proteins 0.000 description 1
- 101150075175 Asgr1 gene Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- FVMMQJUBNMOPPR-WLDMJGECSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]formamide Chemical compound OC[C@H]1OC(O)[C@H](NC=O)[C@@H](O)[C@H]1O FVMMQJUBNMOPPR-WLDMJGECSA-N 0.000 description 1
- RTEOJYOKWPEKKN-HXQZNRNWSA-N N-[(3R,4R,5R,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]propanamide Chemical compound CCC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O RTEOJYOKWPEKKN-HXQZNRNWSA-N 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- JVWLUVNSQYXYBE-UHFFFAOYSA-N Ribitol Natural products OCC(C)C(O)C(O)CO JVWLUVNSQYXYBE-UHFFFAOYSA-N 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101150013568 US16 gene Proteins 0.000 description 1
- 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 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 238000002617 apheresis Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical class OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-L ethenyl-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-L 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- IVVMYMCCLPZNRL-UHFFFAOYSA-N hydrazinylphosphonic acid Chemical class NNP(O)(O)=O IVVMYMCCLPZNRL-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000012405 in silico analysis Methods 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- VDXZNPDIRNWWCW-JFTDCZMZSA-N melittin Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(N)=O)CC1=CNC2=CC=CC=C12 VDXZNPDIRNWWCW-JFTDCZMZSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- RSILPKJOINTLOK-UJRRQQMQSA-N n-[2-[2-[(2r,3r,4r,5r,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyethoxy]ethyl]-3-(4-methyl-2,5-dioxofuran-3-yl)propanamide Chemical group CC(=O)N[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OCCOCCNC(=O)CCC1=C(C)C(=O)OC1=O RSILPKJOINTLOK-UJRRQQMQSA-N 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 210000001927 retinal artery Anatomy 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical group NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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)
-
- 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
-
- 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
- C12N2310/35—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
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3517—Marker; Tag
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562235816P | 2015-10-01 | 2015-10-01 | |
| US62/235,816 | 2015-10-01 | ||
| US201662346304P | 2016-06-06 | 2016-06-06 | |
| US62/346,304 | 2016-06-06 | ||
| US201662383221P | 2016-09-02 | 2016-09-02 | |
| US62/383,221 | 2016-09-02 | ||
| PCT/US2016/054729 WO2017059223A2 (en) | 2015-10-01 | 2016-09-30 | Compositions and methods for inhibiting gene expression of lpa |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021039949A Division JP7116212B2 (ja) | 2015-10-01 | 2021-03-12 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2018529732A JP2018529732A (ja) | 2018-10-11 |
| JP2018529732A5 JP2018529732A5 (enExample) | 2019-11-07 |
| JP6991966B2 true JP6991966B2 (ja) | 2022-02-03 |
Family
ID=58424351
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018516738A Active JP6991966B2 (ja) | 2015-10-01 | 2016-09-30 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
| JP2021039949A Active JP7116212B2 (ja) | 2015-10-01 | 2021-03-12 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
| JP2022096415A Active JP7442574B2 (ja) | 2015-10-01 | 2022-06-15 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
| JP2023199857A Withdrawn JP2024009262A (ja) | 2015-10-01 | 2023-11-27 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021039949A Active JP7116212B2 (ja) | 2015-10-01 | 2021-03-12 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
| JP2022096415A Active JP7442574B2 (ja) | 2015-10-01 | 2022-06-15 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
| JP2023199857A Withdrawn JP2024009262A (ja) | 2015-10-01 | 2023-11-27 | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 |
Country Status (37)
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7718133B2 (en) | 2003-10-09 | 2010-05-18 | 3M Innovative Properties Company | Multilayer processing devices and methods |
| US10246709B2 (en) * | 2016-03-07 | 2019-04-02 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands for therapeutic compounds |
| CA3011668A1 (en) | 2016-09-02 | 2018-03-08 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands |
| ES2932831T3 (es) * | 2017-04-05 | 2023-01-26 | Silence Therapeutics Gmbh | Productos y composiciones |
| JP2020526192A (ja) * | 2017-07-06 | 2020-08-31 | アローヘッド ファーマシューティカルズ インコーポレイテッド | アルファ−ＥＮａＣの発現を阻害するためのＲＮＡｉ剤、および使用方法 |
| WO2019051402A1 (en) * | 2017-09-11 | 2019-03-14 | Arrowhead Pharmaceuticals, Inc. | RNA INTERFERENCE AGENTS AND COMPOSITIONS FOR INHIBITING THE EXPRESSION OF APOLIPOPROTEIN C-III (APOC3) |
| EP3681513A4 (en) * | 2017-09-14 | 2021-09-22 | Arrowhead Pharmaceuticals, Inc. | RNAI AGENTS AND COMPOSITIONS FOR INHIBITING THE EXPRESSION OF ANGIOPOIETIN-LIKE 3 (ANGPTL3) AND METHOD OF USE |
| KR102822647B1 (ko) | 2017-10-04 | 2025-06-19 | 어비디티 바이오사이언시스 인크. | 핵산-폴리펩티드 조성물 및 그의 용도 |
| JP7473472B2 (ja) * | 2017-10-17 | 2024-04-23 | アローヘッド ファーマシューティカルズ インコーポレイテッド | アシアロ糖タンパク質受容体１の発現を阻害するためのＲＮＡｉ剤および組成物 |
| EP3483270A1 (en) * | 2017-11-13 | 2019-05-15 | Silence Therapeutics GmbH | Products and compositions |
| US11319537B2 (en) * | 2017-11-13 | 2022-05-03 | Silence Therapeutics Gmbh | Nucleic acids for inhibiting expression of LPA in a cell |
| MY209138A (en) * | 2018-09-19 | 2025-06-24 | Arrowhead Pharmaceuticals Inc | Rnai agents for inhibiting expression of 17beta-hsd type 13- (hsd17b13), compositions thereof, and methods of use |
| PH12021550801B1 (en) * | 2018-11-13 | 2024-04-26 | Silence Therapeutics Gmbh | Nucleic acids for inhibiting expression of lpa in a cell |
| CN114375296A (zh) * | 2019-06-06 | 2022-04-19 | 艾维迪提生物科学公司 | 核酸多肽组合物及其用途 |
| US20220307024A1 (en) * | 2019-06-17 | 2022-09-29 | Alnylam Pharmaceuticals, Inc. | Delivery of oligonucleotides to the striatum |
| CN112442499A (zh) * | 2019-08-30 | 2021-03-05 | 恩智（广州）医药科技有限公司 | 一种抑制MCM7的siRNA、组合物及其应用 |
| JP2023504744A (ja) * | 2019-12-09 | 2023-02-06 | アムジエン・インコーポレーテツド | ＬＰＡ発現を阻害するためのＲＮＡｉコンストラクト及び方法 |
| MX2022011801A (es) * | 2020-03-23 | 2022-10-07 | Amgen Inc | Anticuerpos monoclonales contra acidos nucleicos modificados quimicamente y usos de los mismos. |
| IL300338A (en) * | 2020-08-05 | 2023-04-01 | Dicerna Pharmaceuticals Inc | Compounds and methods for inhibiting the expression of LPA |
| CN116490195A (zh) * | 2020-10-16 | 2023-07-25 | 赛诺菲 | 用于抑制脂蛋白(a)的RNA组合物和方法 |
| TW202233837A (zh) * | 2020-11-05 | 2022-09-01 | 美商安進公司 | 用靶向ＬＰＡ的ＲＮＡｉ構建體治療動脈粥樣硬化性心血管疾病之方法 |
| WO2022121959A1 (zh) * | 2020-12-09 | 2022-06-16 | 纳肽得有限公司 | siRNA分子及其在治疗冠状动脉疾病中的应用 |
| JP2024500035A (ja) | 2020-12-23 | 2024-01-04 | アルゴノート アールエヌエー リミテッド | 心血管疾患の治療 |
| CN117836307A (zh) | 2021-06-18 | 2024-04-05 | 弘景生物科技有限公司 | 功能化的n-乙酰基半乳糖胺核苷 |
| US11692001B2 (en) | 2021-08-30 | 2023-07-04 | Hongene Biotech Corporation | Functionalized n-acetylgalactosamine analogs |
| US20250283076A1 (en) | 2021-09-14 | 2025-09-11 | Argonaute RNA Limited | Treatment of cardiovascular disease |
| EP4403633A1 (en) * | 2021-09-18 | 2024-07-24 | Genoval Therapeutics Co., Ltd. | Lpa inhibitor and use thereof |
| EP4448540A1 (en) | 2021-12-15 | 2024-10-23 | Hongene Biotech Corporation | Functionalized n-acetylgalactosamine analogs |
| JP2024545222A (ja) * | 2021-12-16 | 2024-12-05 | 上海拓界生物医薬科技有限公司 | ＬＰＡを標的とするｓｉＲＮＡ及び複合体 |
| CN114703184B (zh) * | 2022-03-11 | 2024-06-18 | 厦门甘宝利生物医药有限公司 | Lpa抑制剂及其用途 |
| CN119698469A (zh) * | 2022-08-11 | 2025-03-25 | 益杰立科(上海)生物科技有限公司 | 一种表观编辑靶点的方法及用途 |
| CN115851723B (zh) * | 2022-10-24 | 2023-10-03 | 厦门甘宝利生物医药有限公司 | 一种抑制lpa基因表达的rna抑制剂及其应用 |
| US12116382B2 (en) | 2022-11-28 | 2024-10-15 | Hongene Biotech Corporation | Functionalized N-acetylgalactosamine analogs |
| KR20250130686A (ko) * | 2023-01-13 | 2025-09-02 | 일라이 릴리 앤드 캄파니 | 치료 올리고뉴클레오티드-함유 제약 조성물 및 그를 사용한 투여 요법 |
| CN119384503A (zh) * | 2023-04-03 | 2025-01-28 | 翰森（上海）健康科技有限公司 | 靶向LPA基因的RNAi剂及其用途 |
| WO2024222686A1 (zh) * | 2023-04-24 | 2024-10-31 | 上海京新生物医药有限公司 | 用于抑制LPA表达的RNAi剂及其应用 |
| CN119343449A (zh) * | 2023-05-24 | 2025-01-21 | 云合智药（苏州）生物科技有限公司 | 用于抑制angptl3表达的rnai剂及其应用 |
| WO2024245410A1 (zh) * | 2023-05-31 | 2024-12-05 | 上海拓界生物医药科技有限公司 | 一种靶向LPA的dsRNA及其应用 |
| AU2024279456A1 (en) * | 2023-05-31 | 2025-12-04 | Arrowhead Pharmaceuticals, Inc. | HEPATIC DELIVERY PLATFORMS FOR MULTIMERIC RNAi AGENT CONJUGATES AND METHODS OF USE THEREOF |
| DE102023115075A1 (de) * | 2023-06-07 | 2024-12-12 | B.Braun Avitum Ag | Schlauchrollenpumpe |
| TW202530406A (zh) | 2023-09-21 | 2025-08-01 | 美商Ionis製藥公司 | 用於抑制ｌｐａ的化合物及方法 |
| WO2025082058A1 (zh) * | 2023-10-16 | 2025-04-24 | 润佳(上海)医药技术有限公司 | 一种抑制LPA基因表达的dsRNA及其用途 |
| WO2025087442A1 (zh) * | 2023-10-27 | 2025-05-01 | 北京安龙生物医药有限公司 | 靶向脂蛋白a的寡核苷酸及其用途 |
| WO2025103391A1 (zh) * | 2023-11-15 | 2025-05-22 | 北京加科瑞康医药科技有限公司 | 用于抑制lpa的基因表达的sirna，含其的组合物及其用途 |
| CN120020252A (zh) * | 2023-11-17 | 2025-05-20 | 纳肽得(青岛)生物医药有限公司 | 抑制LPA表达的siRNA及其用途 |
| CN120098993A (zh) * | 2023-12-05 | 2025-06-06 | 广东东阳光药业股份有限公司 | 一种新型的双链siRNA、其缀合物及其用途 |
| CN120485189B (zh) * | 2025-07-16 | 2025-10-17 | 北京悦康科创医药科技股份有限公司 | 靶向调控LPA基因表达的siRNA及其用途 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011141703A1 (en) | 2010-05-12 | 2011-11-17 | Protiva Biotherapeutics Inc. | Compositions and methods for silencing apolipoprotein b |
| JP2014504295A (ja) | 2010-12-17 | 2014-02-20 | アローヘッド リサーチ コーポレイション | ｓｉＲＮＡ用ガラクトースクラスター−薬物動態調節剤標的指向部分 |
| WO2014179625A1 (en) | 2013-05-01 | 2014-11-06 | Isis Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION |
| JP2015522255A (ja) | 2012-05-24 | 2015-08-06 | アイシス ファーマシューティカルズ， インコーポレーテッド | アポリポタンパク質（ａ）発現を調節するための方法および組成物 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL9201440A (nl) | 1992-08-11 | 1994-03-01 | Univ Leiden | Triantennaire clusterglycosiden, hun bereiding en toepassing. |
| US5599706A (en) | 1994-09-23 | 1997-02-04 | Stinchcomb; Dan T. | Ribozymes targeted to apo(a) mRNA |
| WO2000053722A2 (en) | 1999-03-10 | 2000-09-14 | Phogen Limited | Delivery of nucleic acids and proteins to cells |
| CZ302719B6 (cs) * | 2000-12-01 | 2011-09-21 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Izolovaná molekula dvouretezcové RNA, zpusob její výroby a její použití |
| US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
| US7259150B2 (en) * | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
| WO2004081198A2 (en) | 2003-03-12 | 2004-09-23 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Methods for modulating angiogenesis with apelin compositions |
| EP1742958B1 (en) | 2004-03-15 | 2017-05-17 | City of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded rna |
| EP2061443A4 (en) * | 2006-08-18 | 2013-07-24 | Arrowhead Res Corp | POLYCONJUGATE FOR IN VIVO ADMINISTRATION OF POLYNUCLEOTIDES |
| US20100249214A1 (en) | 2009-02-11 | 2010-09-30 | Dicerna Pharmaceuticals | Multiplex dicer substrate rna interference molecules having joining sequences |
| EP2379083B1 (en) | 2008-12-18 | 2017-08-16 | Dicerna Pharmaceuticals, Inc. | Extended dicer substrate agents and methods for the specific inhibition of gene expression |
| ES2562817T3 (es) | 2010-02-24 | 2016-03-08 | Arrowhead Research Corporation | Composiciones para el suministro dirigido de ARNip |
| US8501930B2 (en) | 2010-12-17 | 2013-08-06 | Arrowhead Madison Inc. | Peptide-based in vivo siRNA delivery system |
| CA2816041C (en) | 2010-12-29 | 2019-01-08 | Arrowhead Research Corporation | In vivo polynucleotide delivery conjugates having enzyme sensitive linkages |
| KR20140051357A (ko) | 2011-08-26 | 2014-04-30 | 애로우헤드 리서치 코오포레이션 | Ｉｎ Ｖｉｖｏ 핵산 전달용 폴리(비닐 에스테르) 고분자 |
| IN2014CN03463A (enExample) * | 2011-11-18 | 2015-10-09 | Alnylam Pharmaceuticals Inc | |
| JP2015515530A (ja) | 2012-04-18 | 2015-05-28 | アローヘッド リサーチ コーポレイション | インビボ核酸送達のためのポリ（アクリラート）ポリマー |
| EP2961434A2 (en) * | 2013-02-28 | 2016-01-06 | ImmunoGen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| WO2016149020A1 (en) * | 2015-03-17 | 2016-09-22 | Arrowhead Research Corporation | Rna interference agents |
| JP7021076B2 (ja) | 2015-05-29 | 2022-02-16 | アローヘッド ファーマシューティカルズ インコーポレイテッド | Ｈｉｆ２αの遺伝子発現を阻害する組成物及び方法 |
| HUE051998T2 (hu) * | 2015-07-31 | 2021-04-28 | Alnylam Pharmaceuticals Inc | Transztiretin (TTR) iRNS készítmények és eljárások azok alkalmazása TTR-asszociált betegségek kezelésére vagy megelõzésére |
| US10246709B2 (en) | 2016-03-07 | 2019-04-02 | Arrowhead Pharmaceuticals, Inc. | Targeting ligands for therapeutic compounds |
-
2015
- 2015-10-01 JO JOP/2021/0043A patent/JOP20210043A1/ar unknown
-
2016
- 2016-09-28 JO JOP/2016/0211A patent/JOP20160211B1/ar active
- 2016-09-30 MX MX2018003833A patent/MX2018003833A/es unknown
- 2016-09-30 EP EP21191363.7A patent/EP4029941A1/en active Pending
- 2016-09-30 KR KR1020247036942A patent/KR20240162596A/ko active Pending
- 2016-09-30 MY MYPI2018000440A patent/MY195796A/en unknown
- 2016-09-30 AU AU2016331084A patent/AU2016331084B2/en active Active
- 2016-09-30 EA EA201890864A patent/EA038478B1/ru unknown
- 2016-09-30 US US15/281,309 patent/US9932586B2/en active Active
- 2016-09-30 TW TW111141660A patent/TWI836693B/zh active
- 2016-09-30 CR CR20180231A patent/CR20180231A/es unknown
- 2016-09-30 LT LTEPPCT/US2016/054729T patent/LT3356529T/lt unknown
- 2016-09-30 TW TW113106862A patent/TWI880645B/zh active
- 2016-09-30 CN CN201680057095.8A patent/CN108368506A/zh active Pending
- 2016-09-30 CA CA3000397A patent/CA3000397A1/en active Pending
- 2016-09-30 UY UY0001036926A patent/UY36926A/es active IP Right Grant
- 2016-09-30 HU HUE16852695A patent/HUE055942T2/hu unknown
- 2016-09-30 SG SG10202008530TA patent/SG10202008530TA/en unknown
- 2016-09-30 ES ES16852695T patent/ES2896298T3/es active Active
- 2016-09-30 JP JP2018516738A patent/JP6991966B2/ja active Active
- 2016-09-30 RS RS20211351A patent/RS62523B1/sr unknown
- 2016-09-30 SI SI201631374T patent/SI3356529T1/sl unknown
- 2016-09-30 TN TNP/2018/000094A patent/TN2018000094A1/en unknown
- 2016-09-30 EP EP16852695.2A patent/EP3356529B1/en active Active
- 2016-09-30 HR HRP20211410TT patent/HRP20211410T1/hr unknown
- 2016-09-30 SM SM20210622T patent/SMT202100622T1/it unknown
- 2016-09-30 BR BR112018006489-0A patent/BR112018006489A2/pt active Search and Examination
- 2016-09-30 PL PL16852695T patent/PL3356529T3/pl unknown
- 2016-09-30 TW TW105131823A patent/TWI784934B/zh active
- 2016-09-30 KR KR1020187010095A patent/KR102728481B1/ko active Active
- 2016-09-30 PT PT168526952T patent/PT3356529T/pt unknown
- 2016-09-30 IL IL300438A patent/IL300438A/en unknown
- 2016-09-30 DK DK16852695.2T patent/DK3356529T3/da active
- 2016-09-30 PE PE2018000487A patent/PE20181139A1/es unknown
- 2016-09-30 UA UAA201804593A patent/UA121998C2/uk unknown
- 2016-09-30 WO PCT/US2016/054729 patent/WO2017059223A2/en not_active Ceased
-
2017
- 2017-04-06 MA MA43347A patent/MA43347B1/fr unknown
-
2018
- 2018-02-21 US US15/901,810 patent/US10662427B2/en active Active
- 2018-03-25 IL IL258333A patent/IL258333B/en unknown
- 2018-03-27 MX MX2022013010A patent/MX2022013010A/es unknown
- 2018-03-28 PH PH12018500713A patent/PH12018500713A1/en unknown
- 2018-03-28 CL CL2018000803A patent/CL2018000803A1/es unknown
- 2018-04-05 CO CONC2018/0003678A patent/CO2018003678A2/es unknown
-
2020
- 2020-05-06 US US16/867,925 patent/US20200263179A1/en not_active Abandoned
-
2021
- 2021-03-12 JP JP2021039949A patent/JP7116212B2/ja active Active
- 2021-08-30 ZA ZA2021/06265A patent/ZA202106265B/en unknown
- 2021-11-08 CY CY20211100962T patent/CY1125263T1/el unknown
-
2022
- 2022-02-13 IL IL290566A patent/IL290566B2/en unknown
- 2022-06-15 JP JP2022096415A patent/JP7442574B2/ja active Active
- 2022-12-05 AU AU2022283623A patent/AU2022283623B2/en active Active
-
2023
- 2023-11-27 JP JP2023199857A patent/JP2024009262A/ja not_active Withdrawn
-
2024
- 2024-06-17 US US18/745,289 patent/US20250115907A1/en active Pending
-
2025
- 2025-10-03 AU AU2025242219A patent/AU2025242219A1/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011141703A1 (en) | 2010-05-12 | 2011-11-17 | Protiva Biotherapeutics Inc. | Compositions and methods for silencing apolipoprotein b |
| JP2014504295A (ja) | 2010-12-17 | 2014-02-20 | アローヘッド リサーチ コーポレイション | ｓｉＲＮＡ用ガラクトースクラスター−薬物動態調節剤標的指向部分 |
| JP2015522255A (ja) | 2012-05-24 | 2015-08-06 | アイシス ファーマシューティカルズ， インコーポレーテッド | アポリポタンパク質（ａ）発現を調節するための方法および組成物 |
| WO2014179625A1 (en) | 2013-05-01 | 2014-11-06 | Isis Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION |
Non-Patent Citations (1)
| Title |
|---|
| Journal of Cardiovascular Translational Research，2015年01月，Vol.8，pp.44-53 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7116212B2 (ja) | Ｌｐａの遺伝子発現の阻害のための組成物及び方法 | |
| TWI811238B (zh) | 用於抑制脂蛋白元C-III(APOC3)表現之RNAi試劑及組合物 | |
| CN108064313B (zh) | 用于抑制因子xii的基因表达的组合物和方法 | |
| JP2020505415A (ja) | 第ｘｉｉ因子遺伝子発現を阻害するための組成物および方法 | |
| JP2024086876A (ja) | アシアロ糖タンパク質受容体１の発現を阻害するためのＲＮＡｉ剤および組成物 | |
| EA048832B1 (ru) | Композиции и способы для ингибирования генной экспрессии лпа | |
| HK1259063B (en) | Compositions and methods for inhibiting gene expression of lpa |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A529 | Written submission of copy of amendment under article 34 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A529 Effective date: 20180330 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190926 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190926 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200915 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20201210 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210205 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210312 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210511 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210616 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20211112 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20211208 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6991966 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |