Compositions and methods for modulating angiopoietin-like 3 expression
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
C12N-015/113
C07H-019/20
C07H-015/04
출원번호
US-0959714
(2015-12-04)
등록번호
US-9957292
(2018-05-01)
발명자
/ 주소
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
Freier, Susan M.
Graham, Mark J.
Crooke, Rosanne M.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
Grant IP, Inc.
인용정보
피인용 횟수 :
0인용 특허 :
59
초록▼
Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat,
Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease and/or metabolic disease, or a symptom thereof, 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 having a nucleobase sequence comprising at least 12 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NOs: 1-2, and w
1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 12 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NOs: 1-2, and wherein the conjugate group comprises: 2. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified sugar. 3. The compound of claim 2, wherein at least one modified sugar is a bicyclic sugar. 4. The compound of claim 2, 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. 5. The compound of claim 2, wherein at least one modified sugar is 2′-O-methoxyethyl. 6. The compound of claim 1, wherein the modified oligonucleotide comprises at least one modified nucleobase. 7. The compound of claim 6, wherein the modified nucleobase is a 5-methylcytosine. 8. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 9. The compound of claim 1, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 10. 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. 11. The compound of claim 10, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 12. The compound of claim 10, wherein the modified oligonucleotide comprises at least 2 phosphorothioate internucleoside linkages. 13. The compound of claim 1, wherein the modified oligonucleotide is single stranded. 14. The compound of claim 1, wherein the modified oligonucleotide is double stranded. 15. 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. 16. The compound of claim 15, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 17. The compound of claim 16, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 18. The compound of claim 1, wherein the modified oligonucleotide is 20 linked nucleosides in length and 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, and wherein each cytosine residue is a 5-methylcytosine. 19. The compound of claim 18, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 20. The compound of claim 19, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 21. The compound of claim 1, wherein the modified oligonucleotide consists of 20 linked nucleosides. 22. The compound of claim 1, wherein the modified oligonucleotide comprises the formula GesGeoAeomCeoAeoTdsTdsGdsmCdsmCdsAdsGdsTdsAdsAdsTeomCeoGesmCesAe,wherein “e” indicates a 2′-O-methoxyethyl modified nucleoside, “d” indicates a β-D-2′-deoxyribonucleoside, “s” indicates a phosphorothioate internucleoside linkage, “o” indicates a phosphodiester internucleoside linkage, and “m” indicates a 5-methylcytosine. 23. A composition comprising the compound of claim 1, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 24. A composition comprising the compound of claim 22, or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 25. A method for reducing angiopoietin-like 3 (ANGPTL3) expression in a subject, comprising administering to the subject a compound, or salt thereof, comprising a modified oligonucleotide and a conjugate group, wherein: the modified oligonucleotide consists of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 12 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NOs: 1-2;wherein the conjugate group comprises: and wherein the compound, or salt thereof, reduces the ANGPTL3 expression in the subject. 26. A method for treating, delaying, slowing the progression of and/or ameliorating a cardiovascular and/or metabolic disease, disorder or condition, comprising administering to a subject in need thereof an effective amount of a compound, or salt thereof, comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides having a nucleobase sequence comprising at least 12 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NOs: 1-2, and wherein the conjugate group comprises: whereby administration of the effective amount of the compound, or salt thereof, to the subject in need treats, delays, slows the progression of and/or ameliorates the cardiovascular and/or metabolic disease, disorder or condition. 27. The method of claim 25, wherein the modified oligonucleotide comprises at least one modified sugar. 28. The method of claim 27, wherein at least one modified sugar is a bicyclic sugar. 29. The method of claim 27, 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. 30. The method of claim 27, wherein at least one modified sugar is 2′-O-methoxyethyl. 31. The method of claim 25, wherein the modified oligonucleotide comprises at least one modified nucleobase. 32. The method of claim 31, wherein the modified nucleobase is a 5-methylcytosine. 33. The method of claim 25, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 34. The method of claim 25, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 35. The method of claim 25, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 36. The method of claim 35, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 37. The method of claim 35, wherein the modified oligonucleotide comprises at least 2 phosphorothioate internucleoside linkages. 38. The method of claim 25, wherein the modified oligonucleotide is single stranded. 39. The method of claim 25, wherein the modified oligonucleotide is double stranded. 40. The method of claim 25, 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. 41. The method of claim 40, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 42. The method of claim 41, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 43. The method of claim 25, wherein the modified oligonucleotide is 20 linked nucleosides in length and 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, and wherein each cytosine residue is a 5-methylcytosine. 44. The method of claim 43, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 45. The method of claim 44, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 46. The method of claim 25, wherein the modified oligonucleotide consists of 20 linked nucleosides. 47. The method of claim 25, wherein the modified oligonucleotide comprises the formula GesGeoAeomCeoAeoTdsTdsGdsmCdsmCdsAdsGdsTdsAdsAdsTeomCeoGesmCesAe, wherein “e” indicates a 2′-O-methoxyethyl modified nucleoside, “d” indicates a β-D-2′-deoxyribonucleoside, “s” indicates a phosphorothioate internucleoside linkage, “o” indicates a phosphodiester internucleoside linkage, and “m” indicates a 5-methylcytosine. 48. The method of claim 25, wherein a composition comprising the compound, or salt thereof, is administered to the subject, and the composition comprises a pharmaceutically acceptable carrier or diluent. 49. The method of claim 47, wherein a composition comprising the compound, or salt thereof, is administered to the subject, and the composition comprises a pharmaceutically acceptable carrier or diluent. 50. The method of claim 25, wherein the subject is human. 51. The method of claim 26, wherein the modified oligonucleotide comprises at least one modified sugar. 52. The method of claim 51, wherein at least one modified sugar is a bicyclic sugar. 53. The method of claim 51, 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. 54. The method of claim 51, wherein at least one modified sugar is 2′-O-methoxyethyl. 55. The method of claim 26, wherein the modified oligonucleotide comprises at least one modified nucleobase. 56. The method of claim 55, wherein the modified nucleobase is a 5-methylcytosine. 57. The method of claim 26, wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 58. The method of claim 26, wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide. 59. The method of claim 26, wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 60. The method of claim 59, wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 61. The method of claim 59, wherein the modified oligonucleotide comprises at least 2 phosphorothioate internucleoside linkages. 62. The method of claim 26, wherein the modified oligonucleotide is single stranded. 63. The method of claim 26, wherein the modified oligonucleotide is double stranded. 64. The method 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. 65. The method of claim 64, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 66. The method of claim 65, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 67. The method of claim 26, wherein the modified oligonucleotide is 20 linked nucleosides in length and 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, and wherein each cytosine residue is a 5-methylcytosine. 68. The method of claim 67, wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 69. The method of claim 68, wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 70. The method of claim 26, wherein the modified oligonucleotide consists of 20 linked nucleosides. 71. The method of claim 26, wherein the modified oligonucleotide comprises the formula GesGeoAeomCeoAeoTdsTdsGdsmCdsmCdsAdsGdsTdsAdsAdsTeomCeoGesmCesAe, wherein “e” indicates a 2′-O-methoxyethyl modified nucleoside, “d” indicates a β-D-2′-deoxyribonucleoside, “s” indicates a phosphorothioate internucleoside linkage, “o” indicates a phosphodiester internucleoside linkage, and “m” indicates a 5-methylcytosine. 72. The method of claim 26, wherein a composition comprising the compound, or salt thereof, is administered to the subject, and the composition comprises a pharmaceutically acceptable carrier or diluent. 73. The method of claim 71, wherein a composition comprising the compound, or salt thereof, is administered to the subject, and the composition comprises a pharmaceutically acceptable carrier or diluent. 74. The method of claim 26, wherein the subject is human. 75. The method of claim 26, wherein the disease, disorder or condition is atherosclerosis, hepatic steatosis, obesity, diabetes, dyslipidemia, coronary heart disease, non-alcoholic fatty liver disease (NAFLD), hyperfattyacidemia and/or metabolic syndrome. 76. The method of claim 75, wherein the hepatic steatosis is nonalcoholic steatohepatitis (NASH) and the dyslipidemia is hyperlipidemia, hypercholesterolemia and/or hypertriglyceridemia. 77. The method of claim 75, wherein the disease, disorder or condition is non-alcoholic fatty liver disease (NAFLD). 78. The method of claim 75, wherein the disease, disorder or condition is hepatic steatosis and the hepatic steatosis is nonalcoholic steatohepatitis (NASH). 79. The method of claim 75, wherein the disease, disorder or condition is dyslipidemia and the dyslipidemia is hypercholesterolemia. 80. The method of claim 26, wherein the administering is by parenteral administration. 81. The method of claim 80, wherein the administering is by injection.
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (59)
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.
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.
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.
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.
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.
Cook Phillip Dan (Carlsbad CA) Manoharan Muthiah (Carlsbad CA) Ramasamy Kanda S. (Laguna Hills CA), Substituted purines and oligonucleotide cross-linking.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.