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 .- 124 . (canceled) 
     
     
         125 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides having a nucleobase sequence comprising a portion of at least 12 contiguous nucleobases complementary to an equal length portion of nucleobases 2159-2182 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is complementary to SEQ ID NO: 1. 
     
     
         126 . The compound of  claim 125 , wherein the modified oligonucleotide is a single-stranded oligonucleotide. 
     
     
         127 . The compound of  claim 125 , wherein the nucleobase sequence of the modified oligonucleotide is 80% complementary to SEQ ID NO: 1. 
     
     
         128 . The compound of  claim 125 , wherein the nucleobase sequence of the modified oligonucleotide is 90% complementary to SEQ ID NO: 1. 
     
     
         129 . The compound of  claim 125 , wherein the nucleobase sequence of the modified oligonucleotide is 95% complementary to SEQ ID NO: 1. 
     
     
         130 . The compound of  claim 125 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         131 . The compound of  claim 125 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         132 . The compound of  claim 131 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         133 . The compound of  claim 131 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         134 . The compound of  claim 125 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         135 . The compound of  claim 134 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         136 . The compound of  claim 125 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         137 . The compound of  claim 136 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         138 . The compound of  claim 125 , 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.   
     
     
         139 . The compound of  claim 125 , wherein the modified oligonucleotide consists of 20 linked nucleosides 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 internucleoside linkage is a phosphorothioate linkage.   
     
     
         140 . The compound of  claim 139 , wherein the modified oligonucleotide has a nucleobase sequence that consists of the nucleobase sequence of SEQ ID NO. 109. 
     
     
         141 . A pharmaceutical composition comprising the compound of  claim 140  and a pharmaceutically acceptable carrier or diluent. 
     
     
         142 . A method of reducing DMPK expression in an animal comprising administering to the animal a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to DMPK, wherein expression of DMPK is reduced in the animal. 
     
     
         143 . A method of preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathyin an animal comprising administering to the animal a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to DMPK, wherein the modified oligonucleotide reduces DMPK expression in the animal, thereby preferentially reducing CUGexp DMPK RNA, reducing myotonia or reducing spliceopathy in the animal.