US2013190384A1PendingUtilityA1

Modulation of factor 11 expression

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Assignee: ISIS PHARMACEUTICALS INCPriority: Oct 15, 2008Filed: Dec 4, 2012Published: Jul 25, 2013
Est. expiryOct 15, 2028(~2.3 yrs left)· nominal 20-yr term from priority
Inventors:Susan M. FreierBrett P. MoniaHong ZhangChenguang ZhaoJeffrey R. CrosbyAndrew M. Siwkowski
A61P 7/00A61P 7/02A61P 9/10A61P 9/04A61P 43/00A61P 9/14A61P 9/00A61P 25/00A61P 11/00C12N 15/1137A61K 31/737C12N 2310/3341A61K 31/4545A61K 31/727C12N 2310/315A61K 31/4365A61K 31/713C07H 21/00A61K 31/7125C12N 2310/11C12N 2310/346C12Y 304/21027C12N 2310/321A61K 31/366C12N 2310/341A61K 48/00A61K 31/70C12N 15/113A61K 31/7088
61
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Claims

Abstract

Disclosed herein are antisense compounds and methods for decreasing Factor 11 and treating or preventing thromboembolic complications in an individual in need thereof. Examples of disease conditions that can be ameliorated with the administration of antisense compounds targeted to Factor 11 include thrombosis, embolism, and thromboembolism, such as, deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke. Antisense compounds targeting Factor 11 can also be used as a prophylactic treatment to prevent individuals at risk for thrombosis and embolism.

Claims

exact text as granted — not AI-modified
1 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence that is at least 90% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide. 
     
     
         2 . The compound of  claim 1 , consisting of a single-stranded modified oligonucleotide. 
     
     
         3 . The compound of  claim 2 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to a nucleobase sequence of SEQ ID NO: 1. 
     
     
         4 . The compound of  claim 2 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         5 . The compound of  claim 4 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         6 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         7 . The compound of  claim 6 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         8 . The compound of  claim 7 , wherein each of the at least one bicyclic sugar comprises a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2. 
     
     
         9 . The compound of  claim 7 , wherein each of the at least one bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         10 . The compound of  claim 6 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group. 
     
     
         11 . The compound of  claim 1 , comprising at least one tetrahydropyran modified nucleoside wherein a tetrahydropyran ring replaces the furanose ring. 
     
     
         12 . The compound of  claim 11 , wherein each of the at least one tetrahydropyran modified nucleoside has the structure: 
       
         
           
           
               
               
           
         
         wherein Bx is an optionally protected heterocyclic base moiety. 
       
     
     
         13 . The compound of  claim 2 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         14 . The compound of  claim 13 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         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 immediately adjacent to and 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 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 immediately adjacent and 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 internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.   
     
     
         17 . The compound of  claim 16 , wherein each cytosine is a 5-methylcytosine. 
     
     
         18 . The compound of  claim 17 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         19 - 30 . (canceled) 
     
     
         31 . A composition comprising a compound comprising modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence that is at least 90% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide or a salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         32 . The composition of  claim 31 , wherein said compound consists of a single-stranded oligonucleotide. 
     
     
         33 . The composition of  claim 32 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         34 - 54 . (canceled) 
     
     
         55 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide. 
     
     
         56 . The compound of  claim 18 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide. 
     
     
         57 . The compound of  claim 18 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide. 
     
     
         58 . The composition of  claim 31 , 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 immediately adjacent and 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 internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.   
     
     
         59 . The composition of  claim 58 , wherein each cytosine of the modified oligonucleotide is a 5-methylcytosine. 
     
     
         60 . The composition of  claim 59 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         61 . The composition of  claim 60 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1 as measured over the entirety of the modified oligonucleotide.

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