JPWO2019157531A5 - - Google Patents

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JPWO2019157531A5
JPWO2019157531A5 JP2020542860A JP2020542860A JPWO2019157531A5 JP WO2019157531 A5 JPWO2019157531 A5 JP WO2019157531A5 JP 2020542860 A JP2020542860 A JP 2020542860A JP 2020542860 A JP2020542860 A JP 2020542860A JP WO2019157531 A5 JPWO2019157531 A5 JP WO2019157531A5
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rna
oligomer compound
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１４～１６個の連結ヌクレオシドからなる修飾オリゴヌクレオチドを含むオリゴマー化合物であって、前記修飾オリゴヌクレオチドが、５’領域、中央領域、及び３’領域を有し、
前記５’領域が、４’－２’架橋型の二環式糖部分をそれぞれが含む１～３つの連結ヌクレオシドからなり、
前記３’領域が、４’－２’架橋型の二環式糖部分をそれぞれが含む１～３つの連結ヌクレオシドからなり、
前記中央領域が、９～１０個の連結ヌクレオシドからなり、前記中央領域が、下記の式：
（Ｎｄ）（Ｎｘ）（Ｎｄ）ｎ
を有し、式中、Ｎｘが、２’－ＯＭｅ－β－Ｄ－リボフラノシル糖部分を含むヌクレオシドであり、Ｎｄがそれぞれ、２’－β－Ｄ－デオキシリボシル糖部分を含むヌクレオシドであり、
ｎが、７または８である前記オリゴマー化合物。 An oligomer compound comprising a modified oligonucleotide consisting of 14 to 16 linked nucleosides, wherein the modified oligonucleotide has a 5'region, a central region, and a 3'region.
The 5'region consists of 1 to 3 linked nucleosides, each containing a 4'-2'crosslinked bicyclic sugar moiety.
The 3'region consists of 1 to 3 linked nucleosides, each containing a 4'-2'crosslinked bicyclic sugar moiety.
The central region consists of 9 to 10 linked nucleosides, and the central region is the following formula:
(N d ) (N x ) (N d ) n
In the formula, N x is a nucleoside containing a 2'-OMe-β-D-ribofuranosyl sugar moiety, and N d is a nucleoside containing a 2'-β-D-deoxyribosyl sugar moiety, respectively. ,
The oligomer compound in which n is 7 or 8. 前記５’領域が、３つのヌクレオシドからなる、請求項１に記載のオリゴマー化合物。 The oligomer compound according to claim 1, wherein the 5'region comprises three nucleosides. 前記３’領域が、３つのヌクレオシドからなる、請求項１または請求項２に記載のオリゴマー化合物。 The oligomer compound according to claim 1 or 2, wherein the 3'region comprises three nucleosides. 前記５’領域のそれぞれのヌクレオシドの４’－２’架橋型の二環式糖部分がそれぞれ、ｃＥｔ、ＬＮＡ、及びＥＮＡから独立して選択される、請求項１～３のいずれかに記載のオリゴマー化合物。 13. Oligomer compound. 前記３’領域のそれぞれのヌクレオシドの４’－２’架橋型の二環式糖部分がそれぞれ、ｃＥｔ、ＬＮＡ、及びＥＮＡから独立して選択される、請求項１～４のいずれかに記載のオリゴマー化合物。 13. Oligomer compound. 前記３’領域及び前記５’領域のそれぞれのヌクレオシドの４’－２’架橋型の二環式糖部分がそれぞれ、ｃＥｔである、請求項１～５のいずれかに記載のオリゴマー化合物。 The oligomer compound according to any one of claims 1 to 5, wherein the 4'- 2'crosslinked bicyclic sugar moieties of the respective nucleosides in the 3'region and the 5'region are cEt, respectively. 前記修飾オリゴヌクレオチドのそれぞれのヌクレオシドの核酸塩基がそれぞれ、チミン、ウラシル、グアニン、シトシン、５－メチルシトシン、及びアデニンのうちから独立して選択される、請求項１～６のいずれかに記載のオリゴマー化合物。 The expression according to any one of claims 1 to 6, wherein the nucleobase of each nucleoside of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine, respectively. Oligo compound. ヌクレオシド間結合がそれぞれ、ホスホジエステルヌクレオシド間結合及びホスホロチオエートヌクレオシド間結合のうちから独立して選択される、請求項１～７のいずれかに記載のオリゴマー化合物。 The oligomer compound according to any one of claims 1 to 7, wherein the nucleoside bond is independently selected from the phosphodiester nucleoside bond and the phosphorothioate nucleoside bond, respectively. 前記中央領域内のヌクレオシド間結合の１つが、メトキシプロピルヌクレオシド間結合であり、前記修飾オリゴヌクレオチドにおける残りのヌクレオシド間結合がそれぞれ、ホスホジエステルヌクレオシド間結合及びホスホロチオエートヌクレオシド間結合のうちから独立して選択される、請求項１～８のいずれかに記載のオリゴマー化合物。 One of the nucleoside bonds in the central region is a methoxypropyl nucleoside bond, and the remaining nucleoside bonds in the modified oligonucleotide are independently selected from the phosphodiester nucleoside bonds and the phosphorothioate nucleoside bonds, respectively. The oligomer compound according to any one of claims 1 to 8. 前記修飾オリゴヌクレオチドの核酸塩基配列が、標的ＲＮＡに対して少なくとも８５％、少なくとも９０％、少なくとも９５％、または１００％相補的である、請求項１～９のいずれかに記載のオリゴマー化合物。 The oligomer compound according to any one of claims 1 to 9, wherein the nucleic acid base sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to the target RNA. 前記標的ＲＮＡが、標的ｍＲＮＡまたは標的ｐｒｅ－ｍＲＮＡである、請求項１０に記載のオリゴマー化合物。 The oligomer compound according to claim 10, wherein the target RNA is a target mRNA or a target pre-mRNA. 前記標的ＲＮＡが、マウス、ラット、サル、またはヒトのＰＴＥＮ、ＳＲＢ－１、ＭＹＤ１１、ＨＴＴ、ＳＯＤ１、またはアルファ－シヌクレインのｍＲＮＡではない、請求項１０に記載のオリゴマー化合物。 The oligomer compound of claim 10, wherein the target RNA is not a mouse, rat, monkey, or human PTEN, SRB-1, MYD11, HTT, SOD1, or alpha-synuclein mRNA. 請求項１０～１２のいずれかに記載のオリゴマー化合物であって、
前記標的ＲＮＡが、肝臓において発現する；および／または
前記標的ＲＮＡが、中枢神経系において発現する；および／または
前記標的ＲＮＡが、がん細胞において発現する；および／または
前記標的ＲＮＡが、筋細胞において発現する、
前記オリゴマー化合物。 The oligomer compound according to any one of claims 10 to 12.
The target RNA is expressed in the liver ; and / or
The target RNA is expressed in the central nervous system ; and / or
The target RNA is expressed in cancer cells ; and / or
The target RNA is expressed in muscle cells.
The oligomer compound. 前記標的ＲＮＡが、ＭｅＣＰ２のＲＮＡ、ＤＵＸ４のＲＮＡ、ＨＤＡＣ２のＲＮＡ、ＡＰＰのＲＮＡ、アタキシン１のＲＮＡ、アタキシン２のＲＮＡ、アタキシン３のＲＮＡ、アタキシン６のＲＮＡ、アタキシン７のＲＮＡ、Ｃ９ＯＲＦ７２のＲＮＡ、ＵＢＥ３ＡのＲＮＡ、プリオンのＲＮＡ、ＰＭＰ２２のＲＮＡ、タウのＲＮＡ、ＬＲＲＫ２のＲＮＡ、ＬＩＮＧＯ２のＲＮＡ、ＧＹＳ１のＲＮＡ、ＫＣＮＴ１のＲＮＡ、ＩＲＦ８のＲＮＡ、プログラニュリンのＲＮＡ、またはＧＦＡＰのＲＮＡから選択される、請求項１０～１３のいずれかに記載のオリゴマー化合物。 The target RNAs include MeCP2 RNA, DUX4 RNA, HDAC2 RNA, APP RNA, Ataxin 1 RNA, Ataxin 2 RNA, Ataxin 3 RNA, Ataxin 6 RNA, Ataxin 7 RNA, and C9ORF72 RNA. Selected from UBE3A RNA, prion RNA, PMP22 RNA, tau RNA, LRRK2 RNA, LINGO2 RNA, GYS1 RNA, KCNT1 RNA, IRF8 RNA, progranulin RNA, or GFAP RNA. , The oligomer compound according to any one of claims 10 to 13 . 前記標的ＲＮＡの発現を調節することが、障害または状態の治療と関連する、請求項１０～１４のいずれかに記載のオリゴマー化合物。 The oligomer compound according to any one of claims 10 to 14 , wherein regulating the expression of the target RNA is associated with the treatment of a disorder or condition.
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Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
US201862629632P 2018-02-12 2018-02-12
US62/629,632 2018-02-12
US201862686632P 2018-06-18 2018-06-18
US62/686,632 2018-06-18
US201862713698P 2018-08-02 2018-08-02
US62/713,698 2018-08-02
US201862739088P 2018-09-28 2018-09-28
US62/739,088 2018-09-28
US201862742265P 2018-10-05 2018-10-05
US62/742,265 2018-10-05
US201862746511P 2018-10-16 2018-10-16
US62/746,511 2018-10-16
PCT/US2019/017725 WO2019157531A1 (en) 2018-02-12 2019-02-12 Modified compounds and uses thereof

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Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3067421B1 (en) * 2011-02-08 2018-10-10 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
EP3922722B1 (en) * 2011-08-11 2023-06-28 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof
AU2019218987A1 (en) 2018-02-12 2020-07-23 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
CA3162618A1 (en) 2019-03-20 2020-09-24 Peter Jungsoo PARK Antisense oligonucleotide-based progranulin augmentation therapy in neurodegenerative diseases
WO2021021673A1 (en) 2019-07-26 2021-02-04 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating gfap
JP2022544587A (en) 2019-08-15 2022-10-19 アイオーニス ファーマシューティカルズ， インコーポレーテッド Bond-modified oligomeric compounds and uses thereof
WO2021084495A1 (en) 2019-11-01 2021-05-06 Novartis Ag The use of a splicing modulator for a treatment slowing progression of huntington's disease
WO2021202788A2 (en) * 2020-04-03 2021-10-07 Ionis Pharmaceuticals, Inc. Modified oligomeric compounds and uses thereof
IL302817A (en) 2020-11-18 2023-07-01 Ionis Pharmaceuticals Inc Compounds and methods for modulating angiotensinogen expression
IL304880A (en) 2021-02-12 2023-10-01 Alnylam Pharmaceuticals Inc Superoxide dismutase 1 (sod1) irna compositions and methods of use thereof for treating or preventing superoxide dismutase 1- (sod1-) associated neurodegenerative diseases
TW202304446A (en) 2021-03-29 2023-02-01 瑞士商諾華公司 The use of a splicing modulator for a treatment slowing progression of huntington’s disease
CA3223192A1 (en) 2021-06-18 2022-12-22 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing ifnar1 expression
WO2023044412A1 (en) * 2021-09-17 2023-03-23 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing dnm1l or drp1 expression
AU2021471586A1 (en) * 2021-10-27 2024-05-09 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof
CA3241122A1 (en) * 2021-12-01 2023-06-08 Atalanta Therapeutics, Inc. Compositions and methods for treatment of epilepsies
WO2023122671A2 (en) * 2021-12-22 2023-06-29 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing glycogen synthase 1
WO2023178144A2 (en) 2022-03-16 2023-09-21 Empirico Inc. Galnac compositions for improving sirna bioavailability

Family Cites Families (162)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
FR2575751B1 (en) 1985-01-08 1987-04-03 Pasteur Institut NOVEL ADENOSINE DERIVATIVE NUCLEOSIDES, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS
US4751219A (en) 1985-02-05 1988-06-14 Nederlandse Centrale Organisatie Voor Toegepast-Natuur-Wetenschappelijk Onderzoek Synthetic glycolipides, a process for the preparation thereof and several uses for these synthetic glycolipides
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
WO1988010264A1 (en) 1987-06-24 1988-12-29 Howard Florey Institute Of Experimental Physiology Nucleoside derivatives
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
WO1992002258A1 (en) 1990-07-27 1992-02-20 Isis Pharmaceuticals, Inc. Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
WO1993010820A1 (en) 1991-11-26 1993-06-10 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
TW393513B (en) 1991-11-26 2000-06-11 Isis Pharmaceuticals Inc Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
HU9501994D0 (en) 1993-03-31 1995-09-28 Sterling Winthrop Inc Novel 5'-substituted nucleosides and oligomers produced therefrom
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US6908903B1 (en) 1994-12-07 2005-06-21 Aletheon Pharmaceuticals, Inc. Cluster clearing agents
US6172045B1 (en) 1994-12-07 2001-01-09 Neorx Corporation Cluster clearing agents
US20030119724A1 (en) 1995-11-22 2003-06-26 Ts`O Paul O.P. Ligands to enhance cellular uptake of biomolecules
WO1997020563A1 (en) 1995-11-22 1997-06-12 The Johns-Hopkins University Ligands to enhance cellular uptake of biomolecules
US7875733B2 (en) 2003-09-18 2011-01-25 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation
CN1231675A (en) 1996-09-26 1999-10-13 味之素株式会社 Modified physiologically active proteins and medicinal compositions containing the same
USRE44779E1 (en) 1997-03-07 2014-02-25 Santaris Pharma A/S Bicyclonucleoside and oligonucleotide analogues
JP3756313B2 (en) 1997-03-07 2006-03-15 武 今西 Novel bicyclonucleosides and oligonucleotide analogues
US6770748B2 (en) 1997-03-07 2004-08-03 Takeshi Imanishi Bicyclonucleoside and oligonucleotide analogue
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
CN1273476C (en) 1997-09-12 2006-09-06 埃克西康有限公司 Bi-and tri-cyclic nucleoside, nucleotide and oligonucleotide analoguse
US7572582B2 (en) 1997-09-12 2009-08-11 Exiqon A/S Oligonucleotide analogues
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
ATE356824T1 (en) 1999-05-04 2007-04-15 Santaris Pharma As L-RIBO-LNA ANALOGUE
US6525191B1 (en) 1999-05-11 2003-02-25 Kanda S. Ramasamy Conformationally constrained L-nucleosides
US6383812B1 (en) 1999-05-28 2002-05-07 Academia Sinica Anti liver disease drug R-YEEE and method of synthesizing branched galactose-terminal glycoproteins
US8541548B2 (en) 1999-06-07 2013-09-24 Arrowhead Madison Inc. Compounds and methods for reversible modification of biologically active molecules
US20080281041A1 (en) 1999-06-07 2008-11-13 Rozema David B Reversibly Masked Polymers
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
JP2004536027A (en) 2000-12-01 2004-12-02 ジョーンズ・ホプキンス・ユニーバーシティー Glycosylated / galactosylated peptide conjugates, bifunctional linkers, and nucleotide monomers / polymers, and related compositions and methods of use
WO2002087541A1 (en) 2001-04-30 2002-11-07 Protiva Biotherapeutics Inc. Lipid-based formulations for gene transfer
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
US20100240730A1 (en) 2002-02-20 2010-09-23 Merck Sharp And Dohme Corp. RNA Interference Mediated Inhibition of Gene Expression Using Chemically Modified Short Interfering Nucleic Acid (siNA)
AU2003260289A1 (en) 2002-09-11 2004-04-30 Santaris Pharma A/S Modified pna molecules
EP1562971B1 (en) 2002-11-05 2014-02-12 Isis Pharmaceuticals, Inc. Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation
WO2004044132A2 (en) 2002-11-05 2004-05-27 Isis Pharmaceuticals, Inc. Modified oligonucleotides for use in rna interference
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7851615B2 (en) 2003-04-17 2010-12-14 Alnylam Pharmaceuticals, Inc. Lipophilic conjugated iRNA agents
EP1620544B1 (en) 2003-04-17 2018-09-19 Alnylam Pharmaceuticals Inc. MODIFIED iRNA AGENTS
JPWO2004101619A1 (en) 2003-05-15 2006-10-26 塩野義製薬株式会社 Rational design and synthesis of functional glycopeptides
WO2004106356A1 (en) 2003-05-27 2004-12-09 Syddansk Universitet Functionalized nucleotide derivatives
US7427672B2 (en) 2003-08-28 2008-09-23 Takeshi Imanishi Artificial nucleic acids of n-o bond crosslinkage type
AU2005272816B2 (en) 2004-08-10 2011-08-11 Alnylam Pharmaceuticals, Inc. Chemically modified oligonucleotides
WO2006031461A2 (en) 2004-09-09 2006-03-23 Isis Pharmaceuticals, Inc. Pyrrolidinyl groups for attaching conjugates to oligomeric compounds
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
JP2008527993A (en) 2005-01-24 2008-07-31 アヴァリス・アクチエボラーグ Complex comprising siRNA molecule, shRNA molecule or antisense molecule and functional entity for improved specificity and delivery
CN102908630B (en) 2006-01-27 2014-11-19 Isis制药公司 6-modified bicyclic nucleic acid analogs
US7569686B1 (en) 2006-01-27 2009-08-04 Isis Pharmaceuticals, Inc. Compounds and methods for synthesis of bicyclic nucleic acid analogs
US7666854B2 (en) 2006-05-11 2010-02-23 Isis Pharmaceuticals, Inc. Bis-modified bicyclic nucleic acid analogs
EP2066684B1 (en) 2006-05-11 2012-07-18 Isis Pharmaceuticals, Inc. 5'-modified bicyclic nucleic acid analogs
WO2008022309A2 (en) 2006-08-18 2008-02-21 F. Hoffmann-La Roche Ag Polyconjugates for in vivo delivery of polynucleotides
US8658211B2 (en) 2006-08-18 2014-02-25 Arrowhead Madison Inc. Polyconjugates for in vivo delivery of polynucleotides
EP2410054B2 (en) 2006-10-18 2019-12-11 Ionis Pharmaceuticals, Inc. Antisense compounds
WO2008101157A1 (en) 2007-02-15 2008-08-21 Isis Pharmaceuticals, Inc. 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom
WO2008098788A2 (en) 2007-02-16 2008-08-21 Ktb Tumorforschungsgesellschaft Mbh Receptor and antigen targeted prodrug
US8877917B2 (en) 2007-04-23 2014-11-04 Alnylam Pharmaceuticals, Inc. Glycoconjugates of RNA interference agents
US8278425B2 (en) 2007-05-30 2012-10-02 Isis Pharmaceuticals, Inc. N-substituted-aminomethylene bridged bicyclic nucleic acid analogs
WO2008154401A2 (en) 2007-06-08 2008-12-18 Isis Pharmaceuticals, Inc. Carbocyclic bicyclic nucleic acid analogs
DK2176280T4 (en) 2007-07-05 2015-07-20 Isis Pharmaceuticals Inc 6-Disubstituerede bicykliske nukleinsyreanaloge
ES2439591T3 (en) 2007-08-15 2014-01-23 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
WO2009067647A1 (en) 2007-11-21 2009-05-28 Isis Pharmaceuticals, Inc. Carbocyclic alpha-l-bicyclic nucleic acid analogs
US20090247608A1 (en) 2007-12-04 2009-10-01 Alnylam Pharmaceuticals, Inc. Targeting Lipids
MX2010008394A (en) 2008-01-31 2010-11-12 Alnylam Pharmaceuticals Inc Optimized methods for delivery of dsrna targeting the pcsk9 gene.
EP2265627A2 (en) 2008-02-07 2010-12-29 Isis Pharmaceuticals, Inc. Bicyclic cyclohexitol nucleic acid analogs
WO2009120878A2 (en) 2008-03-26 2009-10-01 Alnylam Pharmaceuticals, Inc. Non-natural ribonucleotides, and methods of use thereof
JP5788312B2 (en) 2008-04-11 2015-09-30 アルニラム ファーマスーティカルズ インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． Site-specific delivery of nucleic acids by combining targeting ligands with endosomal degradable components
JP2012513953A (en) 2008-09-23 2012-06-21 アルニラム ファーマスーティカルズ インコーポレイテッド Chemical modification of monomers and oligonucleotides using cycloaddition
WO2010036698A1 (en) 2008-09-24 2010-04-01 Isis Pharmaceuticals, Inc. Substituted alpha-l-bicyclic nucleosides
KR102264822B1 (en) 2008-11-10 2021-06-14 알닐람 파마슈티칼스 인코포레이티드 Novel lipids and compositions for the delivery of therapeutics
US20120101148A1 (en) 2009-01-29 2012-04-26 Alnylam Pharmaceuticals, Inc. lipid formulation
CA3042927C (en) 2009-05-05 2022-05-17 Arbutus Biopharma Corporation Lipid compositions for the delivery of therapeutic agents
EA028860B1 (en) 2009-06-10 2018-01-31 Арбутус Биофарма Корпорэйшн Improved lipid formulation
WO2010148013A2 (en) 2009-06-15 2010-12-23 Alnylam Pharmaceuticals, Inc. Lipid formulated dsrna targeting the pcsk9 gene
EP2462153B1 (en) 2009-08-06 2015-07-29 Isis Pharmaceuticals, Inc. Bicyclic cyclohexose nucleic acid analogs
TWI458493B (en) 2009-09-25 2014-11-01 Iner Aec Executive Yuan Novel liver-targeting agents and their synthesis
TWI388338B (en) 2009-10-26 2013-03-11 Iner Aec Executive Yuan Method of radiolabelling multivalent glycoside for using as hepatic receptor imaging agent
TWI391144B (en) 2009-10-26 2013-04-01 Iner Aec Executive Yuan A quantification method for remaining liver function with a novel liver receptor imaging agent
WO2011072290A2 (en) 2009-12-11 2011-06-16 The Regents Of The University Of Michigan Targeted dendrimer-drug conjugates
US9198972B2 (en) 2010-01-28 2015-12-01 Alnylam Pharmaceuticals, Inc. Monomers and oligonucleotides comprising cycloaddition adduct(s)
JP6137834B2 (en) 2010-02-24 2017-05-31 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 Composition for targeted delivery of siRNA
US20130109817A1 (en) 2010-03-26 2013-05-02 Mersana Therapeutics, Inc. Modified Polymers for Delivery of Polynucleotides, Method of Manufacture, and Methods of Use Thereof
US8349308B2 (en) 2010-03-26 2013-01-08 Mersana Therapeutics, Inc. Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof
WO2011123621A2 (en) 2010-04-01 2011-10-06 Alnylam Pharmaceuticals Inc. 2' and 5' modified monomers and oligonucleotides
US10913767B2 (en) 2010-04-22 2021-02-09 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising acyclic and abasic nucleosides and analogs
WO2011156278A1 (en) 2010-06-07 2011-12-15 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
US20130236968A1 (en) 2010-06-21 2013-09-12 Alnylam Pharmaceuticals, Inc. Multifunctional copolymers for nucleic acid delivery
JP2013541334A (en) 2010-09-15 2013-11-14 アルニラム ファーマスーティカルズ インコーポレイテッド Modified iRNA agent
EP2640400A4 (en) 2010-11-19 2016-01-20 Sirna Therapeutics Inc Poly(amide) polymers for the delivery of oligonucleotides
US8501930B2 (en) 2010-12-17 2013-08-06 Arrowhead Madison Inc. Peptide-based in vivo siRNA delivery system
WO2012083046A2 (en) 2010-12-17 2012-06-21 Arrowhead Research Corporation Galactose cluster-pharmacokinetic modulator targeting moiety for sirna
BR112013016761B1 (en) 2010-12-29 2021-04-06 F. Hoffmann-La Roche Ag USE OF A COMPOUND, COMPOUND AND PHARMACEUTICAL COMPOSITION
EP3067421B1 (en) 2011-02-08 2018-10-10 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
KR102055331B1 (en) 2011-04-21 2019-12-12 아이오니스 파마수티컬즈, 인코포레이티드 Modulation of hepatitis b virus (hbv) expression
WO2012170347A1 (en) 2011-06-09 2012-12-13 Isis Pharmaceuticals, Inc. Bicyclic nucleosides and oligomeric compounds prepared therefrom
CA3191066A1 (en) 2011-06-21 2012-12-27 Alnylam Pharmaceuticals Inc. Compositions and methods for inhibition of expression of apolipoprotein c-iii (apoc3) genes
EP3922722B1 (en) 2011-08-11 2023-06-28 Ionis Pharmaceuticals, Inc. Selective antisense compounds and uses thereof
KR20140051357A (en) 2011-08-26 2014-04-30 애로우헤드 리서치 코오포레이션 Poly(vinyl ester) polymers for in vivo nucleic acid delivery
EP3640332A1 (en) 2011-08-29 2020-04-22 Ionis Pharmaceuticals, Inc. Oligomer-conjugate complexes and their use
IN2014CN03463A (en) 2011-11-18 2015-10-09 Alnylam Pharmaceuticals Inc
US9243291B1 (en) * 2011-12-01 2016-01-26 Isis Pharmaceuticals, Inc. Methods of predicting toxicity
EP3336189A1 (en) 2012-04-20 2018-06-20 Ionis Pharmaceuticals, Inc. Oligomeric compounds comprising bicyclic nucleotides and uses thereof
TWI595885B (en) 2012-05-02 2017-08-21 喜納製藥公司 Novel tetragalnac containing conjugates and methods for delivery of oligonucleotides
EP3453762B1 (en) 2012-05-02 2021-04-21 Sirna Therapeutics, Inc. Short interfering nucleic acid (sina) compositions
EP2906699A4 (en) 2012-10-11 2016-06-08 Ionis Pharmaceuticals Inc Oligomeric compounds comprising bicyclic nucleosides and uses thereof
EP4052709A1 (en) 2012-10-11 2022-09-07 Ionis Pharmaceuticals, Inc. Methods of treating kennedy's disease
US9175291B2 (en) 2012-10-11 2015-11-03 Isis Pharmaceuticals Inc. Modulation of androgen receptor expression
DK2906256T3 (en) 2012-10-12 2018-11-19 Ionis Pharmaceuticals Inc SELECTIVE ANTISENSE COMPOUNDS AND APPLICATIONS THEREOF
US20160138014A1 (en) * 2012-10-12 2016-05-19 Isis Pharmaceuticals, Inc. Antisense compounds and uses thereof
NZ631552A (en) 2013-05-01 2017-02-24 Ionis Pharmaceuticals Inc Compositions and methods for modulating hbv expression
TW201536329A (en) 2013-08-09 2015-10-01 Isis Pharmaceuticals Inc Compounds and methods for modulation of dystrophia myotonica-protein kinase (DMPK) expression
WO2015106128A2 (en) 2014-01-09 2015-07-16 Alnylam Pharmaceuticals, Inc. MODIFIED RNAi AGENTS
US10208947B2 (en) 2014-03-26 2019-02-19 Rockwell Automation Technologies, Inc. Cloud-level analytics for boiler networks
WO2015168172A1 (en) * 2014-04-28 2015-11-05 Isis Pharmaceuticals, Inc. Linkage modified oligomeric compounds
US9688707B2 (en) 2014-12-30 2017-06-27 Ionis Pharmaceuticals, Inc. Bicyclic morpholino compounds and oligomeric compounds prepared therefrom
EP3653712B1 (en) 2015-02-04 2022-11-30 F. Hoffmann-La Roche AG Tau antisense oligomers and uses thereof
CN107636159B (en) 2015-02-04 2022-06-14 百时美施贵宝公司 Method for selecting therapeutic molecules
WO2016127002A1 (en) 2015-02-04 2016-08-11 Bristol-Myers Squibb Company Lna oligonucleotides with alternating flanks
ES2848377T3 (en) 2015-02-26 2021-08-09 Ionis Pharmaceuticals Inc Allele-specific modulators of RHODOPSIN P23H
CA2978100C (en) 2015-04-03 2023-10-17 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating tmprss6 expression
MA43072A (en) 2015-07-22 2018-05-30 Wave Life Sciences Ltd COMPOSITIONS OF OLIGONUCLEOTIDES AND RELATED PROCESSES
US20180273577A1 (en) 2015-09-24 2018-09-27 Ionis Pharmaceuticals, Inc. Modulators of kras expression
RS61529B9 (en) 2015-11-12 2024-04-30 Hoffmann La Roche Oligonucleotides for inducing paternal ube3a expression
JP7049271B2 (en) 2016-06-17 2022-04-06 エフ．ホフマン－ラ ロシュ アーゲー In vitro nephrotoxicity screening assay
WO2017216325A1 (en) 2016-06-17 2017-12-21 F. Hoffmann-La Roche Ag In vitro nephrotoxicity screening assay
MX2018015722A (en) 2016-07-01 2019-05-27 Hoffmann La Roche Antisense oligonucleotides for modulating htra1 expression.
US11180756B2 (en) 2017-03-09 2021-11-23 Ionis Pharmaceuticals Morpholino modified oligomeric compounds
US20190055564A1 (en) 2017-06-01 2019-02-21 F. Hoffmann-La Roche Ag Antisense oligonucleotides for modulating htra1 expression
AR112779A1 (en) 2017-08-08 2019-12-11 Wave Life Sciences Ltd NUCLEOTIDE COMPOSITIONS AND RELATED METHODS
AU2018350693B2 (en) * 2017-10-16 2021-03-04 F. Hoffmann-La Roche Ag Nucleic acid molecule for reduction of PAPD5 and PAPD7 mRNA for treating hepatitis B infection
CA3085964A1 (en) 2018-01-12 2019-07-18 Roche Innovation Center Copenhagen A/S Alpha-synuclein antisense oligonucleotides and uses thereof
PE20201501A1 (en) 2018-01-12 2020-12-29 Bristol Myers Squibb Co ANTI-SENSE OLIGONUCLEOTIDES ACTING ON ALPHA-SINUCLEIN, AND USES OF THESE
KR20200140240A (en) 2018-01-12 2020-12-15 브리스톨-마이어스 스큅 컴퍼니 Antisense oligonucleotides targeting alpha-synuclein and uses thereof
AU2019218987A1 (en) 2018-02-12 2020-07-23 Ionis Pharmaceuticals, Inc. Modified compounds and uses thereof
US11241451B2 (en) 2018-03-02 2022-02-08 Ionis Pharmaceuticals, Inc. Modulators of IRF4 expression
AU2019252667A1 (en) 2018-04-11 2020-10-01 Ionis Pharmaceuticals, Inc. Modulators of EZH2 expression
WO2019245957A1 (en) 2018-06-18 2019-12-26 Ionis Pharmaceuticals, Inc. Linkage modified oligomeric compounds
JP7102557B2 (en) 2018-07-03 2022-07-19 エフ．ホフマン－ラ ロシュ アーゲー Oligonucleotide for TAU expression regulation
EP3917497A4 (en) 2019-02-01 2023-06-07 Wave Life Sciences Ltd. Oligonucleotide compositions and methods thereof
EP3947677A1 (en) 2019-04-04 2022-02-09 F. Hoffmann-La Roche AG Oligonucleotides for modulating atxn2 expression
CA3137741A1 (en) 2019-04-25 2020-10-29 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof
AU2020267775A1 (en) 2019-05-09 2021-12-02 Wave Life Sciences Ltd. Oligonucleotide compositions and methods of use thereof
WO2020245233A1 (en) 2019-06-06 2020-12-10 F. Hoffmann-La Roche Ag Antisense oligonucleotides targeting atxn3

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