JP6478632B2 - ペプチドオリゴヌクレオチドコンジュゲート - Google Patents
ペプチドオリゴヌクレオチドコンジュゲート Download PDFInfo
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- JP6478632B2 JP6478632B2 JP2014509281A JP2014509281A JP6478632B2 JP 6478632 B2 JP6478632 B2 JP 6478632B2 JP 2014509281 A JP2014509281 A JP 2014509281A JP 2014509281 A JP2014509281 A JP 2014509281A JP 6478632 B2 JP6478632 B2 JP 6478632B2
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 180
- 108091034117 Oligonucleotide Proteins 0.000 title description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 172
- 235000001014 amino acid Nutrition 0.000 claims description 171
- 229940024606 amino acid Drugs 0.000 claims description 171
- 150000001413 amino acids Chemical class 0.000 claims description 151
- 229910052739 hydrogen Inorganic materials 0.000 claims description 111
- -1 guanidinyl Chemical group 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 102
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 89
- 150000007523 nucleic acids Chemical class 0.000 claims description 86
- 102000039446 nucleic acids Human genes 0.000 claims description 84
- 108020004707 nucleic acids Proteins 0.000 claims description 84
- 230000000692 anti-sense effect Effects 0.000 claims description 79
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 70
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 60
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 57
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 52
- 239000004471 Glycine Substances 0.000 claims description 51
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 235000009697 arginine Nutrition 0.000 claims description 44
- 239000004475 Arginine Substances 0.000 claims description 41
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 41
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- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 40
- 210000004027 cell Anatomy 0.000 claims description 39
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 claims description 32
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 claims description 32
- 125000005647 linker group Chemical group 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 28
- 210000004899 c-terminal region Anatomy 0.000 claims description 28
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 25
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 23
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical group NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000747 amidyl group Chemical group [H][N-]* 0.000 claims description 14
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 13
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 13
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical group NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 12
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 12
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 12
- 150000001484 arginines Chemical class 0.000 claims description 12
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 12
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- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 12
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- 230000009385 viral infection Effects 0.000 claims description 12
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 10
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 10
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 10
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 208000018360 neuromuscular disease Diseases 0.000 claims description 9
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 8
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 229940009976 deoxycholate Drugs 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 150000004713 phosphodiesters Chemical class 0.000 claims description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- 229940099352 cholate Drugs 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 5
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 5
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 230000001268 conjugating effect Effects 0.000 claims description 5
- 229930182817 methionine Natural products 0.000 claims description 5
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 5
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 4
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 4
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- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 4
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| US13/107,528 US9238042B2 (en) | 2010-05-13 | 2011-05-13 | Antisense modulation of interleukins 17 and 23 signaling |
| US13/107,528 | 2011-05-13 | ||
| PCT/US2011/061282 WO2012150960A1 (en) | 2011-05-05 | 2011-11-17 | Peptide oligonucleotide conjugates |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021167107A1 (ja) | 2020-02-22 | 2021-08-26 | Ｊｃｒファーマ株式会社 | ヒトトランスフェリンレセプター結合ペプチド |
| WO2023026994A1 (ja) | 2021-08-21 | 2023-03-02 | 武田薬品工業株式会社 | ヒトトランスフェリンレセプター結合ペプチド－薬物コンジュゲート |
| WO2023027125A1 (ja) | 2021-08-24 | 2023-03-02 | ペプチドリーム株式会社 | ヒトトランスフェリンレセプター結合抗体－ペプチドコンジュゲート |
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| DK1766010T3 (da) | 2004-06-28 | 2011-06-06 | Univ Western Australia | Antisense-oligonukleotider til induktion af exon-skipping og fremgangsmåder til anvendelse deraf |
| ES2852549T3 (es) | 2005-02-09 | 2021-09-13 | Sarepta Therapeutics Inc | Composición antisentido para tratamiento de la atrofia muscular |
| CA2660523C (en) | 2006-08-11 | 2019-03-19 | Prosensa Technologies B.V. | Methods and means for treating dna repeat instability associated genetic disorders |
| US20100016215A1 (en) | 2007-06-29 | 2010-01-21 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
| ES2914775T3 (es) | 2007-10-26 | 2022-06-16 | Academisch Ziekenhuis Leiden | Medios y métodos para contrarresta trastornos del músculo |
| EP2119783A1 (en) | 2008-05-14 | 2009-11-18 | Prosensa Technologies B.V. | Method for efficient exon (44) skipping in Duchenne Muscular Dystrophy and associated means |
| KR20190079702A (ko) | 2008-10-24 | 2019-07-05 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | Dmd를 위한 다중 엑손 스키핑 조성물 |
| NZ626359A (en) | 2009-11-12 | 2016-02-26 | Univ Western Australia | Antisense molecules and methods for treating pathologies |
| TWI541024B (zh) | 2010-09-01 | 2016-07-11 | 日本新藥股份有限公司 | 反義核酸 |
| US20130085139A1 (en) | 2011-10-04 | 2013-04-04 | Royal Holloway And Bedford New College | Oligomers |
| WO2013074834A1 (en) | 2011-11-18 | 2013-05-23 | Sarepta Therapeutics, Inc. | Functionally-modified oligonucleotides and subunits thereof |
| EP2785729B1 (en) | 2011-11-30 | 2020-11-04 | Sarepta Therapeutics, Inc. | Oligonucleotides for treating expanded repeat diseases |
| US9944926B2 (en) | 2011-11-30 | 2018-04-17 | Sarepta Therapeutics, Inc. | Induced exon inclusion in spinal muscle atrophy |
| TR201809173T4 (tr) | 2011-12-08 | 2018-07-23 | Sarepta Therapeutics Inc | İnsan LMNA'sını hedef alan oligonükleotid analogları. |
| AU2013212758A1 (en) | 2012-01-27 | 2014-08-14 | Biomarin Technologies B.V. | RNA modulating oligonucleotides with improved characteristics for the treatment of Duchenne and Becker muscular dystrophy |
| RS56319B1 (sr) | 2012-04-23 | 2017-12-29 | Biomarin Tech Bv | Oligonukleotidi koji moduliraju rnk sa poboljšanim karakteristikama za lečenje neuromišićnih poremećaja |
| EP3885439A1 (en) | 2012-12-20 | 2021-09-29 | Sarepta Therapeutics, Inc. | Improved exon skipping compositions for treating muscular dystrophy |
| US9856474B2 (en) | 2013-01-16 | 2018-01-02 | Iowa State University Research Foundation, Inc. | Deep intronic target for splicing correction on spinal muscular atrophy gene |
| HUE042218T2 (hu) * | 2013-03-14 | 2019-06-28 | Sarepta Therapeutics Inc | Exonátugrást elõsegítõ készítmények izomdisztrófia kezelésére |
| CN105378081B (zh) * | 2013-03-14 | 2019-06-14 | 萨勒普塔医疗公司 | 用于治疗肌营养不良的外显子跳跃组合物 |
| CN105307723A (zh) | 2013-03-15 | 2016-02-03 | 萨勒普塔医疗公司 | 改进的用于治疗肌营养不良的组合物 |
| EP3015467A4 (en) | 2013-05-24 | 2016-11-02 | Ajinomoto Kk | PROCESS FOR THE PRODUCTION OF MORPHOLINO-OLIGONUCLEOTIDE |
| CA2922838A1 (en) | 2013-09-05 | 2015-03-12 | Sarepta Therapeutics, Inc. | Antisense-induced exon2 inclusion in acid alpha-glucosidase |
| WO2015097600A2 (en) | 2013-12-24 | 2015-07-02 | Sentiss Pharma Private Limited | Topical brimonidine tartrate ophthalmic solution |
| MY193708A (en) | 2014-03-12 | 2022-10-26 | Nippon Shinyaku Co Ltd | Antisense nucleic acids |
| KR101661277B1 (ko) * | 2014-03-17 | 2016-09-30 | 제주광어주식회사 | 한 개의 뉴크레오타이드 염기 변화를 통한 약독화 바이러스성 출혈패혈증 바이러스 |
| EP3143141B1 (en) | 2014-05-16 | 2019-10-02 | Oregon State University | Antisense antibacterial compounds and methods |
| EP3569252B1 (en) | 2014-05-19 | 2021-12-15 | Oregon State University | Antisense antibacterial compounds and methods |
| AU2015372560B2 (en) | 2014-12-31 | 2021-12-02 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| US20180216111A1 (en) * | 2015-02-27 | 2018-08-02 | Sarepta Therapeutics, Inc. | Antisense-induced exon2 inclusion in acid alpha-glucosidase |
| MA41795A (fr) | 2015-03-18 | 2018-01-23 | Sarepta Therapeutics Inc | Exclusion d'un exon induite par des composés antisens dans la myostatine |
| US10675356B2 (en) * | 2015-05-19 | 2020-06-09 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
| WO2016196670A1 (en) | 2015-06-01 | 2016-12-08 | Sarepta Therapeutics, Inc. | Antisense-induced exon exclusion in type vii collagen |
| US11020417B2 (en) | 2015-06-04 | 2021-06-01 | Sarepta Therapeutics, Inc | Methods and compounds for treatment of lymphocyte-related diseases and conditions |
| JP6978406B2 (ja) * | 2015-08-05 | 2021-12-08 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 均質オリゴマーを調製するためのキラル試薬 |
| EP3341480A1 (en) * | 2015-08-28 | 2018-07-04 | Sarepta Therapeutics, Inc. | Modified antisense oligomers for exon inclusion in spinal muscular atrophy |
| EP3336098B1 (en) * | 2015-09-10 | 2021-08-11 | IUCF-HYU (Industry-University Cooperation Foundation Hanyang University) | Skin permeable peptide and method for using same |
| WO2017062835A2 (en) | 2015-10-09 | 2017-04-13 | Sarepta Therapeutics, Inc. | Compositions and methods for treating duchenne muscular dystrophy and related disorders |
| GB2545898B (en) | 2015-12-21 | 2019-10-09 | Sutura Therapeutics Ltd | Improved drug delivery by conjugating oligonucleotides to stitched/stapled peptides |
| WO2017112888A1 (en) | 2015-12-23 | 2017-06-29 | David Greenberg | Antisense antibacterial compounds and methods |
| EP3394261A4 (en) | 2015-12-23 | 2019-11-27 | Oregon State University | ANTISENSE ANTIBACTERIAL COMPOUNDS AND ASSOCIATED METHODS |
| WO2017184529A1 (en) | 2016-04-18 | 2017-10-26 | Sarepta Therapeutics, Inc. | Antisense oligomers and methods of using the same for treating diseases associated with the acid alpha-glucosidase gene |
| JP7042255B2 (ja) * | 2016-04-29 | 2022-03-25 | サレプタ セラピューティクス， インコーポレイテッド | ヒトｌｍｎａを標的にするオリゴヌクレオチド類縁体 |
| WO2017205879A2 (en) * | 2016-05-24 | 2017-11-30 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| SG11201810143PA (en) * | 2016-06-30 | 2019-01-30 | Sarepta Therapeutics Inc | Exon skipping oligomers for muscular dystrophy |
| KR20230110811A (ko) | 2016-12-19 | 2023-07-25 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근육 이상증에 대한 엑손 스킵핑 올리고머 결합체 |
| MD3554554T2 (ro) * | 2016-12-19 | 2022-12-31 | Sarepta Therapeutics Inc | Conjugați de oligomeri de omitere a exonului, pentru distrofie musculară |
| NZ755438A (en) | 2016-12-19 | 2023-05-26 | Sarepta Therapeutics Inc | Exon skipping oligomer conjugates for muscular dystrophy |
| TW201919682A (zh) | 2017-08-08 | 2019-06-01 | 西班牙商阿爾米雷爾有限公司 | 活化Ｎｒｆ２路徑的新穎化合物 |
| EA201991450A1 (ru) * | 2017-09-22 | 2019-12-30 | Сарепта Терапьютикс, Инк. | Конъюгаты олигомеров для пропуска экзона при мышечной дистрофии |
| AU2018337854A1 (en) * | 2017-09-22 | 2020-03-19 | Katarzyna JASTRZEBSKA | Thiomorpholino oligonucleotides for the treatment of muscular dystrophy |
| EP3687547A1 (en) | 2017-09-28 | 2020-08-05 | Sarepta Therapeutics, Inc. | Combination therapies for treating muscular dystrophy |
| WO2019067979A1 (en) | 2017-09-28 | 2019-04-04 | Sarepta Therapeutics, Inc. | POLYTHERAPIES FOR TREATING MUSCLE DYSTROPHY |
| JP2020536058A (ja) | 2017-09-28 | 2020-12-10 | サレプタ セラピューティクス， インコーポレイテッド | 筋ジストロフィーを処置するための併用療法 |
| JP7320500B2 (ja) * | 2017-10-17 | 2023-08-03 | サレプタ セラピューティクス， インコーポレイテッド | アンチセンス送達のための細胞透過性ペプチド |
| WO2019079637A2 (en) | 2017-10-18 | 2019-04-25 | Sarepta Therapeutics, Inc. | ANTISENSE OLIGOMERIC COMPOUNDS |
| US20210102205A1 (en) * | 2018-04-26 | 2021-04-08 | Sarepta Therapeutics, Inc. | Exon skipping oligomers and oligomer conjugates for muscular dystrophy |
| US20220251551A1 (en) * | 2018-06-13 | 2022-08-11 | Sarepta Therapeutics, Inc. | Exon skipping oligomers for muscular dystrophy |
| EP4219717A3 (en) | 2018-06-13 | 2023-12-20 | Sarepta Therapeutics, Inc. | Exon skipping oligomers for muscular dystrophy |
| TW202020153A (zh) | 2018-07-27 | 2020-06-01 | 美商薩羅塔治療公司 | 用於肌肉萎縮症之外顯子跳躍寡聚物 |
| EP3829597A4 (en) * | 2018-07-30 | 2022-05-18 | Sarepta Therapeutics, Inc. | TRIMER PEPTIDES FOR ANTISENSE ADMINISTRATION |
| GB201812980D0 (en) * | 2018-08-09 | 2018-09-26 | Univ Oxford Innovation Ltd | Cell-penetrating peptides |
| JP2022528298A (ja) * | 2018-12-07 | 2022-06-10 | オックスフォード ユニバーシティ イノベーション リミテッド | リンカー |
| JP2022511055A (ja) | 2018-12-13 | 2022-01-28 | サレプタ セラピューティクス， インコーポレイテッド | 筋ジストロフィーに対するエクソンスキッピングオリゴマーコンジュゲート |
| GB201821269D0 (en) | 2018-12-28 | 2019-02-13 | Nippon Shinyaku Co Ltd | Myostatin signal inhibitor |
| JP2022528725A (ja) | 2019-04-18 | 2022-06-15 | サレプタ セラピューティクス， インコーポレイテッド | 筋ジストロフィーを治療するための組成物 |
| CN110724180B (zh) * | 2019-10-17 | 2021-08-20 | 山东大学 | 一种抑制新生血管生成的多肽及其应用 |
| JPWO2021132591A1 (ko) | 2019-12-26 | 2021-07-01 | ||
| WO2021174019A1 (en) | 2020-02-28 | 2021-09-02 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating smn2 |
| EP4112083A1 (en) | 2020-02-28 | 2023-01-04 | Nippon Shinyaku Co., Ltd. | Antisense nucleic acid inducing skipping of exon 51 |
| US20240024414A1 (en) * | 2020-09-21 | 2024-01-25 | Icahn School Of Medicine At Mount Sinai | Archaea l30 proteins as universal influenza virus therapeutics |
| EP4267191A1 (en) | 2020-12-23 | 2023-11-01 | Sarepta Therapeutics, Inc. | Compositions comprising exon skipping oligonucleotide conjugates for treating muscular dystrophy |
| CA3211038A1 (en) * | 2021-02-12 | 2022-08-18 | Oxford University Innovation Limited | Cell-penetrating peptide conjugates and methods of their use |
| WO2022232478A1 (en) | 2021-04-30 | 2022-11-03 | Sarepta Therapeutics, Inc. | Treatment methods for muscular dystrophy |
| JPWO2022270585A1 (ko) | 2021-06-23 | 2022-12-29 | ||
| IL310001A (en) | 2021-07-08 | 2024-03-01 | Nippon Shinyaku Co Ltd | sediment suppressant |
| WO2023282344A1 (ja) | 2021-07-08 | 2023-01-12 | 日本新薬株式会社 | 腎毒性軽減剤 |
| EP4368186A1 (en) | 2021-07-08 | 2024-05-15 | Nippon Shinyaku Co., Ltd. | Nephrotoxicity reducing agent |
| CA3233242A1 (en) | 2021-09-30 | 2023-04-06 | Sarepta Therapeutics, Inc. | Antisense oligonucleotides having one or more abasic units |
| WO2023070086A1 (en) | 2021-10-22 | 2023-04-27 | Sarepta Therapeutics, Inc. | Morpholino oligomers for treatment of peripheral myelin protein 22 related diseases |
| WO2023178230A1 (en) | 2022-03-17 | 2023-09-21 | Sarepta Therapeutics, Inc. | Phosphorodiamidate morpholino oligomer conjugates |
| WO2024064237A2 (en) | 2022-09-21 | 2024-03-28 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
Family Cites Families (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215942B1 (en) | 1985-03-15 | 1995-07-12 | Antivirals Inc. | Polynucleotide assay reagent and method |
| US5166315A (en) | 1989-12-20 | 1992-11-24 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
| US5521063A (en) | 1985-03-15 | 1996-05-28 | Antivirals Inc. | Polynucleotide reagent containing chiral subunits and methods of use |
| US5217866A (en) | 1985-03-15 | 1993-06-08 | Anti-Gene Development Group | Polynucleotide assay reagent and method |
| US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
| US5506337A (en) | 1985-03-15 | 1996-04-09 | Antivirals Inc. | Morpholino-subunit combinatorial library and method |
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| JPH07501204A (ja) | 1991-06-28 | 1995-02-09 | マサチューセッツ インスティテュート オブ テクノロジー | 局所的オリゴヌクレオチド療法 |
| JP2702285B2 (ja) | 1992-08-21 | 1998-01-21 | バイオジェン，インコーポレイテッド | Ｔａｔ由来の輸送ポリペプチド |
| JPH0915828A (ja) | 1995-07-03 | 1997-01-17 | Fuji Photo Film Co Ltd | 写真処理システム用ペーパーカッター |
| US6245747B1 (en) | 1996-03-12 | 2001-06-12 | The Board Of Regents Of The University Of Nebraska | Targeted site specific antisense oligodeoxynucleotide delivery method |
| US6306993B1 (en) | 1997-05-21 | 2001-10-23 | The Board Of Trustees Of The Leland Stanford, Jr. University | Method and composition for enhancing transport across biological membranes |
| WO1999005302A1 (en) * | 1997-07-24 | 1999-02-04 | The Perkin-Elmer Corporation | Conjugates of transporter peptides and nucleic acid analogs, and their use |
| DE19933492B4 (de) * | 1999-07-16 | 2008-01-10 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Konjugat zur Vermittlung eines zell-, kompartiment- oder membranspezifischen Transports von Wirksubstanzen, Verfahren zu dessen Herstellung und dessen Verwendung |
| US20020009491A1 (en) | 2000-02-14 | 2002-01-24 | Rothbard Jonathan B. | Compositions and methods for enhancing drug delivery across biological membranes and tissues |
| ATE437647T1 (de) | 2001-02-16 | 2009-08-15 | Cellgate Inc | Transporter mit beabstandeten arginin-teilchen |
| US20030224353A1 (en) | 2001-10-16 | 2003-12-04 | Stein David A. | Antisense antiviral agent and method for treating ssRNA viral infection |
| DK2351844T3 (da) | 2003-04-29 | 2014-09-22 | Sarepta Therapeutics Inc | Præparater til forøgelse af transport- og antisense-effektivitet af nukleinsyreanalog i celler |
| EP1654363B1 (en) | 2003-08-05 | 2010-12-15 | AVI BioPharma, Inc. | Oligonucleotide analog and method for treating flavivirus infections |
| US20050171044A1 (en) | 2003-12-24 | 2005-08-04 | Stein David A. | Oligonucleotide compound and method for treating nidovirus infections |
| EP1750775A2 (en) * | 2004-05-04 | 2007-02-14 | Nastech Pharmaceutical Company Inc. | Compositions and methods for enhancing delivery of nucleic acids into cells and for modifying expression of target genes in cells |
| US20050288246A1 (en) * | 2004-05-24 | 2005-12-29 | Iversen Patrick L | Peptide conjugated, inosine-substituted antisense oligomer compound and method |
| DK1766010T3 (da) | 2004-06-28 | 2011-06-06 | Univ Western Australia | Antisense-oligonukleotider til induktion af exon-skipping og fremgangsmåder til anvendelse deraf |
| US8129352B2 (en) | 2004-09-16 | 2012-03-06 | Avi Biopharma, Inc. | Antisense antiviral compound and method for treating ssRNA viral infection |
| US8357664B2 (en) | 2004-10-26 | 2013-01-22 | Avi Biopharma, Inc. | Antisense antiviral compound and method for treating influenza viral infection |
| US7524829B2 (en) | 2004-11-01 | 2009-04-28 | Avi Biopharma, Inc. | Antisense antiviral compounds and methods for treating a filovirus infection |
| US7838657B2 (en) | 2004-12-03 | 2010-11-23 | University Of Massachusetts | Spinal muscular atrophy (SMA) treatment via targeting of SMN2 splice site inhibitory sequences |
| ES2852549T3 (es) | 2005-02-09 | 2021-09-13 | Sarepta Therapeutics Inc | Composición antisentido para tratamiento de la atrofia muscular |
| EP3308788B1 (en) | 2005-06-23 | 2018-10-24 | Biogen MA Inc. | Compositions and methods for modulation of smn2 splicing |
| EP1937278B1 (en) | 2005-09-08 | 2012-07-25 | AVI BioPharma, Inc. | Antisense antiviral compound and method for treating picornavirus infection |
| US8524676B2 (en) | 2005-09-08 | 2013-09-03 | Sarepta Therapeutics, Inc. | Method for treating enterovirus or rhinovirus infection using antisense antiviral compounds |
| ATE467688T1 (de) | 2006-03-07 | 2010-05-15 | Avi Biopharma Inc | Antivirale antisense-verbindung und verfahren zur behandlung von arenavirus-infektion |
| AU2007297861A1 (en) | 2006-05-10 | 2008-03-27 | Avi Biopharma, Inc. | Oligonucleotide analogs having cationic intersubunit linkages |
| CA2660523C (en) | 2006-08-11 | 2019-03-19 | Prosensa Technologies B.V. | Methods and means for treating dna repeat instability associated genetic disorders |
| CA2981308C (en) | 2006-09-21 | 2020-12-22 | University Of Rochester | Compositions and methods related to protein displacement therapy for myotonic dystrophy |
| WO2008062830A1 (fr) | 2006-11-24 | 2008-05-29 | Hykes Laboratories Llc | Composé de spiroquinone et composition pharmaceutique |
| WO2009005783A1 (en) * | 2007-06-28 | 2009-01-08 | Blanchette Rockefeller Neurosciences Institute | Peptides, compositions and methods for reducing beta-amyloid-mediated apoptosis |
| WO2009005793A2 (en) * | 2007-06-29 | 2009-01-08 | Avi Biopharma, Inc. | Tissue specific peptide conjugates and methods |
| US20100016215A1 (en) * | 2007-06-29 | 2010-01-21 | Avi Biopharma, Inc. | Compound and method for treating myotonic dystrophy |
| CA2704261C (en) | 2007-11-15 | 2015-05-26 | Avi Biopharma, Inc. | Method of synthesis of morpholino oligomers |
| EP2235175A4 (en) * | 2007-12-20 | 2012-04-25 | Angiochem Inc | POLYPEPTIDE-NUCLEIC ACID CONJUGATES AND USES THEREOF |
| US20110130346A1 (en) * | 2008-05-30 | 2011-06-02 | Isis Innovation Limited | Peptide conjugates for delvery of biologically active compounds |
| KR20190079702A (ko) | 2008-10-24 | 2019-07-05 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | Dmd를 위한 다중 엑손 스키핑 조성물 |
| WO2010072228A1 (en) * | 2008-12-22 | 2010-07-01 | Xigen S.A. | Novel transporter constructs and transporter cargo conjugate molecules |
| WO2010120820A1 (en) | 2009-04-13 | 2010-10-21 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulation of smn2 splicing |
| EP3643783A1 (en) | 2009-06-17 | 2020-04-29 | Biogen MA Inc. | Compositions and methods for modulation of smn2 splicing in a subject |
| EP3023496B1 (en) * | 2010-05-13 | 2020-07-29 | Sarepta Therapeutics, Inc. | Compounds which modulate interleukins 17 and 23 signaling activity |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021167107A1 (ja) | 2020-02-22 | 2021-08-26 | Ｊｃｒファーマ株式会社 | ヒトトランスフェリンレセプター結合ペプチド |
| WO2023026994A1 (ja) | 2021-08-21 | 2023-03-02 | 武田薬品工業株式会社 | ヒトトランスフェリンレセプター結合ペプチド－薬物コンジュゲート |
| WO2023027125A1 (ja) | 2021-08-24 | 2023-03-02 | ペプチドリーム株式会社 | ヒトトランスフェリンレセプター結合抗体－ペプチドコンジュゲート |
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