Compound and method for treating myotonic dystrophy

Abstract

Provided are 9-base morpholino antisense compounds targeted to polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA, and related methods for treating myotonic dystrophy DM1.

1 . An antisense compound for treating myotonic dystrophy DM1, consisting of a 9-base phosphorodiamidate morpholino antisense oligonucleotide,
 wherein at least one and up to about 1 per every 2 intersubunit linkage(s) contains a pendant cationic group, and   wherein the 9 bases are complementary to polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA and have the base sequence of SEQ ID NO:5 or SEQ ID NO:9.   
     
     
         2 . The antisense compound of  claim 1 , wherein the cationic group comprises an optionally substituted piperazino group. 
     
     
         3 . The antisense compound of  claim 1 , wherein the oligonucleotide is conjugated to a cell-penetrating peptide. 
     
     
         4 . A method of treating myotonic dystrophy DM1 in a mammalian subject, comprising administering to the subject a 9-base phosphorodiamidate morpholino antisense oligonucleotide,
 wherein at least one and up to about 1 per every 2 intersubunit linkage(s) contains a pendant cationic group, and   wherein the 9 bases are complementary to polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA and have the base sequence of SEQ ID NO:5 or SEQ ID NO:9,   and repeating said administering at least once every one week to 3 months.   
     
     
         5 . The method of  claim 4 , wherein the cationic group comprises an optionally substituted piperazino group. 
     
     
         6 . The method of  claim 4 , wherein the oligonucleotide is conjugated to a cell-penetrating peptide. 
     
     
         7 . The method of  claim 4 , wherein said administering is by intravenous or subcutaneous injection to the subject, at a dose between 1-20 mg/kg body weight antisense compound. 
     
     
         8 . The method of  claim 4 , wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for improvement in skeletal or heart muscle performance. 
     
     
         9 . The method of  claim 4 , wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for improvement in heart conduction properties. 
     
     
         10 . The method of  claim 4 , wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for reduction in serum creatine kinase.