Modulation of Dystrophia Myotonica-Protein Kinase (DMPK) Expression

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of a DMPK mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathy in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate type 1 myotonic dystrophy, or a symptom thereof.

1 .- 22 . (canceled) 
     
     
         23 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 85% complementary to at least 12 contiguous nucleobases of:
 an equal length portion of nucleobases 178-233 of SEQ ID NO:1;   an equal length portion of nucleobases 232-253 of SEQ ID NO:1;   an equal length portion of nucleobases 279-299 of SEQ ID NO:1;   an equal length portion of nucleobases 366-399 of SEQ ID NO:1;   an equal length portion of nucleobases 519-541 of SEQ ID NO:1;   an equal length portion of nucleobases 923-975 of SEQ ID NO:1;   an equal length portion of nucleobases 1073-1105 of SEQ ID NO:1;   an equal length portion of nucleobases 1171-1196 of SEQ ID NO:1;   an equal length portion of nucleobases 1178-1206 of SEQ ID NO:1;   an equal length portion of nucleobases 1215-1246 of SEQ ID NO:1;   an equal length portion of nucleobases 1263-1324 of SEQ ID NO:1;   an equal length portion of nucleobases 1706-1734 of SEQ ID NO:1;   an equal length portion of nucleobases 1743-1763 of SEQ ID NO:1;   an equal length portion of nucleobases 1932-1979 of SEQ ID NO:1;   an equal length portion of nucleobases 1981-2003 of SEQ ID NO:1;   an equal length portion of nucleobases 2077-2108 of SEQ ID NO:1;   an equal length portion of nucleobases 2152-2173 of SEQ ID NO:1;   an equal length portion of nucleobases 2159-2182 of SEQ ID NO:1;   an equal length portion of nucleobases 2174-2196 of SEQ ID NO:1;   an equal length portion of nucleobases 2426-2447 of SEQ ID NO:1;   an equal length portion of nucleobases 2450-2518 of SEQ ID NO:1;   an equal length portion of nucleobases 2679-2725 of SEQ ID NO:1;   an equal length portion of nucleobases 1251-1303 of SEQ ID NO:2;   an equal length portion of nucleobases 1305-1326 of SEQ ID NO:2;   an equal length portion of nucleobases 1352-1372 of SEQ ID NO:2;   an equal length portion of nucleobases 3762-3795 of SEQ ID NO:2;   an equal length portion of nucleobases 4170-4192 of SEQ ID NO:2;   an equal length portion of nucleobases 5800-5852 of SEQ ID NO:2;   an equal length portion of nucleobases 6124-6149 of SEQ ID NO:2;   an equal length portion of nucleobases 6168-6199 of SEQ ID NO:2;   an equal length portion of nucleobases 6216-6277 of SEQ ID NO:2;   an equal length portion of nucleobases 11979-12007 of SEQ ID NO:2;   an equal length portion of nucleobases 12016-12036 of SEQ ID NO:2;   an equal length portion of nucleobases 12993-13042 of SEQ ID NO:2;   an equal length portion of nucleobases 13044-13066 of SEQ ID NO:2;   an equal length portion of nucleobases 13140-13171 of SEQ ID NO:2; or   an equal length portion of nucleobases 13215-13236 of SEQ ID NO:2.   
     
     
         24 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked wherein the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of any of the sequences recited in SEQ ID NOs: 12-156, 160-697, or 802-837. 
     
     
         25 . The compound of  claim 23 , wherein the modified oligonucleotide is a single-stranded oligonucleotide. 
     
     
         26 . The compound of  claim 23 , wherein the nucleobase sequence of the modified oligonucleotide is 90% or 100% complementary to SEQ ID NOs: 1-2 or 801. 
     
     
         27 . The compound of  claim 23 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         28 . The compound of  claim 23 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         29 . The compound of  claim 23 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         30 . The compound of  claim 23 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         31 . The compound of  claim 30 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         32 . The compound of  claim 30 , wherein at least one modified sugar comprises a 2′-Omethoxyethyl. 
     
     
         33 . The compound of  claim 23 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         34 . The compound of  claim 33 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         35 . The compound of  claim 23 , 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.   
     
     
         36 . The compound of  claim 35 , wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises:
 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′-Omethoxyethyl sugar;   and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         37 . The compound of  claim 23 , wherein the compound consists of 20 linked nucleosides. 
     
     
         38 . The compound of  claim 23 , wherein the compound comprises a conjugate group. 
     
     
         39 . A composition comprising the compound of  claim 23  and a pharmaceutically acceptable carrier or diluent. 
     
     
         40 . A method of treating a DMPK related disease or a symptom thereof in an animal, wherein the method comprises administering to said animal a therapeutically effective amount of the compound of  claim 23  or the composition of  claim 39 . 
     
     
         41 . The method of  claim 40 , wherein the DMPK related disease or a symptom thereof is:
 a. myotonia, or   b. spliceopathy.   
     
     
         42 . The method of  claim 41 , wherein the DMPK related disease or a symptom thereof is type 1 myotonic dystrophy. 
     
     
         43 . The method of  claim 42 , wherein the DMPK related disease or a symptom thereof is MBNL dependent spliceopathy.