RU2016104824A - Композиции для модулирования экспрессии тау-белка - Google Patents
Композиции для модулирования экспрессии тау-белка Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims 7
- 102000013498 tau Proteins Human genes 0.000 title 1
- 108010026424 tau Proteins Proteins 0.000 title 1
- 239000002777 nucleoside Substances 0.000 claims 28
- 150000001875 compounds Chemical class 0.000 claims 18
- 125000003835 nucleoside group Chemical group 0.000 claims 16
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 10
- 108091034117 Oligonucleotide Proteins 0.000 claims 10
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims 4
- 150000003839 salts Chemical class 0.000 claims 4
- 208000004051 Chronic Traumatic Encephalopathy Diseases 0.000 claims 2
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 2
- 125000002619 bicyclic group Chemical group 0.000 claims 2
- 230000000295 complement effect Effects 0.000 claims 2
- 208000017004 dementia pugilistica Diseases 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 230000004770 neurodegeneration Effects 0.000 claims 2
- 150000002829 nitrogen Chemical class 0.000 claims 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 2
- 159000000000 sodium salts Chemical group 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 235000021092 sugar substitutes Nutrition 0.000 claims 2
- 239000003765 sweetening agent Substances 0.000 claims 2
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 208000003098 Ganglion Cysts Diseases 0.000 claims 1
- 108091093037 Peptide nucleic acid Proteins 0.000 claims 1
- 208000005400 Synovial Cyst Diseases 0.000 claims 1
- 208000034799 Tauopathies Diseases 0.000 claims 1
- 230000007850 degeneration Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010015037 epilepsy Diseases 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
- 150000004713 phosphodiesters Chemical class 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 1
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- 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
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- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
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- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
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- C12N2310/00—Structure or type of the nucleic acid
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- C12N2310/11—Antisense
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- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
- C12N2310/3525—MOE, methoxyethoxy
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
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Claims (51)
1. Соединение, содержащее модифицированный олигонуклеотид, состоящий из 12-50 связанных нуклеозидов и имеющий последовательность азотистых оснований, содержащую по меньшей мере 8 последовательных азотистых оснований согласно любой из последовательностей азотистых оснований из SEQ ID NO: 20-2565, при этом последовательность азотистых оснований модифицированного олигонуклеотида по меньшей мере на 90% комплементарна SEQ ID NO: 1.
2. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид представляет собой гэпмер.
3. Соединение по п. 1, отличающееся тем, что последовательность азотистых оснований модифицированного олигонуклеотида по меньшей мере на 91%, по меньшей мере на 92%, по меньшей мере на 93%, по меньшей мере на 94%, по меньшей мере на 95%, по меньшей мере на 96%, по меньшей мере на 97%, по меньшей мере на 98%, по меньшей мере на 99% или 100% комплементарна SEQ ID NO: 1.
4. Соединение по п.1, состоящее из одноцепочечного модифицированного олигонуклеотида.
5. Соединение по п.1, отличающееся тем, что по меньшей мере одна межнуклеозидная связь представляет собой модифицированную межнуклеозидную связь, и при этом необязательно (а) по меньшей мере одна модифицированная межнуклеозидная связь представляет собой тиофосфатную межнуклеозидную связь; или (b) по меньшей мере одна межнуклеозидная связь представляет собой фосфодиэфирную межнуклеозидную связь.
6. Соединение по п.1, отличающееся тем, что по меньшей мере один нуклеозид содержит модифицированное азотистое основание, и при этом необязательно модифицированное азотистое основание представляет собой 5-метилцитозин.
7. Соединение по п.1, отличающееся тем, что по меньшей мере один нуклеозид модифицированного олигонуклеотида содержит модифицированный сахар, при этом необязательно (а) по меньшей мере один модифицированный сахар представляет собой бициклический сахар; или (b) по меньшей мере один модифицированный сахар содержит 2'-O-метоксиэтильную группу или 2'-O-метильную группу.
8. Соединение по п. 7, отличающееся тем, что бициклический сахар содержит химический мостик между 2' и 4' позициями сахарного 4'-CH2-N(R)-O-2' мостика, причем R независимо выбран из Н, C1-С6 алкила и C1-С6 алкокси.
9. Соединение по п. 8, отличающееся тем, что по меньшей мере один химический мостик представляет собой:
(a) 4'-CH(R)-O-2' и где R представляет собой метил;
(b) 4'-CH(R)-O-2' и где R представляет собой Н; или
(c) 4'-CH(R)-O-2' и где R представляет собой -СН2-О-СН3.
10. Соединение по п. 1, отличающееся тем, что по меньшей мере один нуклеозид модифицированного олигонуклеотида содержит сахарный суррогат, при этом необязательно по меньшей мере один сахарный суррогат представляет собой морфолино или пептидную нуклеиновую кислоту.
11. Соединение по п. 1, отличающееся тем, что по модифицированный олигонуклеотид содержит:
a) 5'-крыло, содержащее от 1 до 6 нуклеозидов, и при этом каждый нуклеозид 5'-крыла содержит модифицированный сахар;
3'-крыло, содержащее от 1 до 6 нуклеозидов, и при этом каждый нуклеозид 3'-крыла содержит модифицированный сахар; и
гэп, содержащий от 8 до 15 нуклеозидов, и при этом каждый нуклеозид гэпа представляет собой дезоксинуклеозид;
b) гэп, состоящий из 10 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 5 связанных нуклеозидов; и
3'-крыло, состоящее из 5 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид каждого крыла содержит модифицированный сахар;
c) гэп, состоящий из 9 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 5 связанных нуклеозидов; и
3'-крыло, состоящее из 5 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид каждого крыла содержит модифицированный сахар;
d) гэп, состоящий из 7 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 5 связанных нуклеозидов; и
3'-крыло, состоящее из 6 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид из каждого крыла содержит модифицированный сахар;
e) гэп, состоящий из 8 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 5 связанных нуклеозидов; и
3'-крыло, состоящее из 5 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид из каждого крыла содержит модифицированный сахар;
f) гэп, состоящий из 8 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 4 связанных нуклеозидов; и
3'-крыло, состоящее из 6 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид из каждого крыла содержит модифицированный сахар; или
g) гэп, состоящий из 8 связанных дезоксинуклеозидов;
5'-крыло, состоящее из 6 связанных нуклеозидов; и
3'-крыло, состоящее из 4 связанных нуклеозидов;
причем гэп располагается между 5'-крылом и 3'-крылом, и при этом каждый нуклеозид из каждого крыла содержит модифицированный сахар.
12. Соединение по п. 1, отличающееся тем, что соединение содержит группу конъюгата.
13. Композиция, содержащая соединение по любому из пп. 1-12 и по меньшей мере один из фармацевтически приемлемого носителя или разбавителя.
14. Композиция по п. 13, отличающаяся тем, что фармацевтически приемлемый разбавитель представляет собой фосфатный буфер (PBS).
15. Композиция по п. 13, отличающаяся тем, что модифицированный олигонуклеотид соединения представляет собой соль.
16. Композиция по п. 13, отличающаяся тем, что модифицированный олигонуклеотид представляет собой соль.
17. Композиция по п. 15, отличающаяся тем, что соль представляет собой соль натрия.
18. Композиция по п. 16, отличающаяся тем, что соль представляет собой соль натрия.
19. Применение соединения по любому из пп. 1-12 для терапии.
20. Применение соединения по любому из пп. 1-12 для лечения нейродегенеративного заболевания, расстройства или состояния, при этом нейродегенеративное заболевание, расстройство или состояние необязательно выбрано из таупатии, болезни Альцгеймера, лобно-височной деменции (ЛВД), ФТДП-17, прогрессирующего надъядерного паралича (ПНП), хронической травматической энцефалопатии (ХТЭ), кортикобазальной ганглиозной дегенерации (КГД), эпилепсии или синдрома Драве.
21. Применение по п. 19, отличающееся тем, что введение соединения предотвращает, лечит, улучшает или замедляет прогрессирование тау-сопутствующего заболевания, расстройства или состояния.
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
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US201361856551P | 2013-07-19 | 2013-07-19 | |
US61/856,551 | 2013-07-19 | ||
US201361879621P | 2013-09-18 | 2013-09-18 | |
US61/879,621 | 2013-09-18 | ||
US201361885371P | 2013-10-01 | 2013-10-01 | |
US61/885,371 | 2013-10-01 | ||
US201462014486P | 2014-06-19 | 2014-06-19 | |
US62/014,486 | 2014-06-19 | ||
PCT/US2014/047486 WO2015010135A2 (en) | 2013-07-19 | 2014-07-21 | Compositions for modulating tau expression |
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US (4) | US9683235B2 (ru) |
EP (2) | EP3910060A1 (ru) |
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