Compositions and methods for modulating apolipoprotein C-III expression
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
C12N-015/113
C12N-015/11
A61K-031/7088
A61K-031/713
출원번호
US-0839521
(2015-08-28)
등록번호
US-9932581
(2018-04-03)
발명자
/ 주소
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
Graham, Mark J.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
Grant IP, Inc.
인용정보
피인용 횟수 :
0인용 특허 :
119
초록▼
Provided herein are oligomeric compounds with conjugate groups targeting apoplipoprotein C-III (ApoCIII). In certain embodiments, the ApoCIII targeting oligomeric compounds are conjugated to N-Acetylgalactosamine Also disclosed herein are conjugated oligomeric compounds targeting ApoCIII for use in
Provided herein are oligomeric compounds with conjugate groups targeting apoplipoprotein C-III (ApoCIII). In certain embodiments, the ApoCIII targeting oligomeric compounds are conjugated to N-Acetylgalactosamine Also disclosed herein are conjugated oligomeric compounds targeting ApoCIII for use in decreasing ApoCIII to treat, prevent, or ameliorate diseases, disorders or conditions related to ApoCIII. Certain diseases, disorders or conditions related to ApoCIII include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The conjugated oligomeric compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.
대표청구항▼
1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of nucleobases 1 to 3532 o
1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of nucleobases 1 to 3532 or 3553 to 3958 of SEQ ID NO: 3; and wherein the conjugate group comprises: 2. The compound of claim 1, wherein the modified oligonucleotide consists of 20 linked nucleosides. 3. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar. 4. The compound of claim 3, wherein at least one modified sugar is a bicyclic sugar. 5. The compound of claim 3, wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH2)n—O-2′ bridge, wherein n is 1 or 2. 6. The compound of claim 3, wherein at least one modified sugar is 2′-O-methoxyethyl. 7. The compound of claim 1, wherein at least one nucleoside comprises a modified nucleobase. 8. The compound of claim 7, wherein the modified nucleobase is a 5-methylcytosine. 9. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 10. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 11. The compound of claim 1, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 12. The compound of claim 11, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 13. The compound of claim 11, wherein the modified oligonucleotide comprises at least two phosphorothioate internucleoside linkages. 14. The compound of claim 1, wherein the modified oligonucleotide is single-stranded. 15. The compound of claim 1, wherein the modified oligonucleotide is double stranded. 16. The compound of claim 1, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides;a 5′ wing segment consisting of linked nucleosides;a 3′ wing segment consisting of linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 17. The compound of claim 16, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 18. The compound of claim 17, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 19. The compound of claim 2, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 19, 20, 22-26, 30-32, 36-40, 42-48, 51-68, 73-86, 88-96, 209, 210, 213-221. 20. The compound of claim 19, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 21. The compound of claim 20, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 22. The compound of claim 19, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides;a 5′ wing segment consisting of five linked nucleosides;a 3′ wing segment consisting of five linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage in the gap segment is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine. 23. The compound of claim 22, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 24. A composition comprising the compound of claim 1, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 25. A composition comprising the compound of claim 22, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 26. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to an equal length portion of nucleobases in the coding region, the 5′ UTR, a translation initiation region, a translation termination region, an intron, an intron/exon junction, or an exon/intron junction of SEQ ID NO: 3; and wherein the conjugate group comprises: 27. The compound of claim 26, wherein the modified oligonucleotide consists of 20 linked nucleosides. 28. The compound of claim 26, wherein the modified oligonucleotide comprises at least one modified sugar. 29. The compound of claim 28, wherein at least one modified sugar is a bicyclic sugar. 30. The compound of claim 28, wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH2)n—O-2′ bridge, wherein n is 1 or 2. 31. The compound of claim 28, wherein at least one modified sugar is 2′-O-methoxyethyl. 32. The compound of claim 26, wherein at least one nucleoside comprises a modified nucleobase. 33. The compound of claim 32, wherein the modified nucleobase is a 5-methylcytosine. 34. The compound of claim 26, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 35. The compound of claim 26, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 36. The compound of claim 26, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 37. The compound of claim 36, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 38. The compound of claim 36, wherein the modified oligonucleotide comprises at least two phosphorothioate internucleoside linkages. 39. The compound of claim 26, wherein the modified oligonucleotide is single-stranded. 40. The compound of claim 26, wherein the modified oligonucleotide is double stranded. 41. The compound of claim 26, wherein the modified oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides;a 5′ wing segment consisting of linked nucleosides;a 3′ wing segment consisting of linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 42. The compound of claim 41, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 43. The compound of claim 42, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 44. The compound of claim 27, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 19, 20, 22-26, 30-32, 36-40, 42-48, 51-67, 89-96, 209, 210, 213-218. 45. The compound of claim 44, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 46. The compound of claim 45, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 47. The compound of claim 44, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides;a 5′ wing segment consisting of five linked nucleosides;a 3′ wing segment consisting of five linked nucleosides;wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage in the gap segment is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine. 48. The compound of claim 47, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 49. A composition comprising the compound of claim 26, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 50. A composition comprising the compound of claim 47, or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (119)
Buhr Chris A. ; Matteucci Mark, 2' Modified Oligonucleotides.
Huynh Dinh Tam (Croissy/Seine FRX) Gouyette Catherine (Vanves FRX) Igolen Jean (Le Mesnil St. Denis FRX), 2,N6-disubstituted and 2,N6-trisubstituted adenosine-3′-phosphoramidites.
Cook Philip D. (Carlsbad CA) Delecki Daniel J. (Radnor PA) Guinosso Charles (Vista CA), Acyclic nucleoside analogs and oligonucleotide sequences containing them.
Sanghvi Yogesh S. (Carlsbad CA) Cook Phillip D. (Carlsbad CA), Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling.
Cook Phillip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA) Vasseur Jean J. (San Marcos CA) Debart Francoise (Montpellier FRX), Backbone modified oligonucleotide analogues.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Altmann Karl-Heinz (Basel CHX) Imwinkelried Rene (Brig-Glis CHX) Eschenmoser Albert (Kusnacht CHX), Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use.
Ferrara, Napoleone; Gerber, Hans-Peter; Kowalski, Joe; Pisabarro, Maria Teresa; Sherman, Daniel Eric, Composition comprising and method of using angiopoietin-like protein 3 ANGPTL3.
Ferrara,Napoleone; Gerber,Hans Peter; Kowalski,Joe; Pisabarro,Maria Teresa; Sherman,Daniel Eric, Composition comprising and method of using angiopoietin-like protein 3 Angptl3.
Bhat, Balkrishen; Xia, Jie; Seth, Punit P.; Vasquez, Guillermo; Migawa, Michael T.; Allerson, Charles; Prakash, Thazha P.; Swayze, Eric E., Compounds and methods for synthesis of bicyclic nucleic acid analogs.
Ts'o, Paul O. P.; Duff, Robert; Deamond, Scott, Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use.
Ts'O,Paul O. P.; Duff,Robert; Deamond,Scott, Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and methods of use.
Froehler Brian (Belmont CA) Matteucci Mark (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified purines.
Froehler Brian (Belmont CA) Wagner Rick (Belmont CA) Matteucci Mark (Burlingame CA) Jones Robert J. (Millbrae CA) Gutierrez Arnold J. (Sandy Lane CA) Pudlo Jeff (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines.
Rogers Thomas E. (Manchester MO) Gray Steven H. (Ellisville MO) Devadas Balekudru (Chesterfield MO) Adams Steven P. (St. Charles MO), Improved probes using nucleosides containing 3-dezauracil analogs.
Benner Steven A. (Hadlaubstrasse 151 CH-8006 Zurich CHX), Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Froehler Brian ; Wagner Rick ; Matteucci Mark ; Jones Robert J. ; Gutierrez Arnold J. ; Pudlo Jeff, Methods of using oligomers containing modified pyrimidines.
Yurkovetskiy, Aleksandr; Yin, Mao; Lowinger, Timothy B.; Cabral, Carolina B.; Hammond, Charles E.; Stevenson, Cheri A., Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof.
Ts\o Paul O. P. (2117 Folkstone Rd. Lutherville MD 21093) Miller Paul S. (225 Hopkins Rd. Baltimore MD 21212), Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof.
Cook Philip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA), Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression.
Baxter Anthony D. (Northwich GB2) Baylis Eric K. (Stockport GB2) Collingwood Stephen P. (Westhoughton GB2) Taylor Roger J. (Stretford GB2) Mesmaeker Alain (Kanerkinden CHX) Schmit Chantal (Basel CHX), Nucleoside phosphinate compounds and compositions.
Letsinger Robert L. (Wilmette IL) Gryaznov Sergei M. (San Mateo CA), Oligodeoxyribonucleotides including 3′-aminonucleoside-phosphoramidate linkages and terminal 3′-amino groups.
Smith Lloyd M. (South Pasadena CA) Fung Steven (Palo Alto CA) Kaiser ; Jr. Robert J. (Glendale CA), Oligonucleotides possessing a primary amino group in the terminal nucleotide.
Lebleu Bernard (Montpellier FRX) Bayard Bernard (Castelnau Le Lez FRX), Oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini.
Rozema, David B.; Wakefield, Darren H.; Lewis, David L.; Wolff, Jon A.; Blokhin, Andrei V.; Benson, Jonathan D.; Carlson, Jeffrey C.; Hadwiger, Philipp; Kitas, Eric A.; Hoffmann, Torsten; Jahn-Hofmann, Kerstin; Mohr, Peter; Mueller, Hans Martin; Ott, Guenther; Roehl, Ingo, Peptide-based in vivo siRNA delivery system.
Misiura Konrad (Lodz PLX) Gait Michael (Cambridge GB3), Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic.
Rozema, David B.; Hagstrom, James E.; Klein, Jason; Lewis, David L.; Monahan, Sean D.; Wakefield, Darren H.; Wolff, Jon A.; Wong, So, Polyconjugates for in vivo delivery of polynucleotides.
Urdea Michael S. (Alamo CA) Horn Thomas (Berkeley CA), Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Ramsay Shaw Barbara (Durham NC), Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Hawkins Mary E. (Potomac MD) Pfleiderer Wolfgang (Konstanz MD DEX) Davis Michael D. (Rockville MD) Balis Frank (Bethesda MD), Pteridine nucleotide analogs as fluorescent DNA probes.
Van Ness Jeffrey (Bothell WA) Petrie Charles R. (Woodinville WA) Tabone John C. (Bothell WA) Vermeulen Nicolaas M. J. (Woodinville WA), Solid supports for nucleic acid hybridization assays.
Cook Phillip Dan (Carlsbad CA) Manoharan Muthiah (Carlsbad CA) Ramasamy Kanda S. (Laguna Hills CA), Substituted purines and oligonucleotide cross-linking.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR), Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.