Oligomers

Abstract

Certain disclosed oligomers induce exon skipping during processing of myostatin pre-mRNA. The oligomers may be in a vector or encoded by the vector. The vector is used for inducing exon skipping during processing of myostatin pre-mRNA. A therapeutically effective amount of the oligomer may be administered to a subject patient such that exon skipping during processing of myostatin pre-mRNA is induced. The administration to a subject may be used in order to increase or maintain muscle mass, or slowing degeneration of muscle mass in the subject. The administration to a subject may ameliorate muscle wasting conditions, such as muscular dystrophy. Examples of such muscular dystrophies which may be so treated include Becker's muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy, myotonic muscular dystrophy, and oculopharyngeal muscular dystrophy

1 . An oligomer for inducing exon skipping during processing of myostatin pre-mRNA, the oligomer comprising at least 20 contiguous bases of a base sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO. 1) 
                 
                 
                 
                 
               
                     
                    1) 
                   XCXCGACGGGXCXCAAAXAXAXCCAXAGXX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 2) 
                 
                 
                 
                 
               
                     
                    2) 
                   XGXACCGXCXXXCAXAGGXXXGAXGAGXCX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 3) 
                 
                 
                 
                 
               
                     
                    3) 
                   CCXGGGXXCAXGXCAAGXXXCAGAGAXCGG; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 4) 
                 
                 
                 
                 
               
                     
                    4) 
                   CAGCCCAXCXXCXCCXGGXCCXGGGAAGGX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 5) 
                 
                 
                 
                 
               
                     
                    5) 
                   XCXXGACGGGXCXGAGAXAXAXCCACAGXX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 6) 
                 
                 
                 
                 
               
                     
                    6) 
                   XGXACCGXCXXXCAXGGGXXXGAXGAGXCX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 7) 
                 
                 
                 
                 
               
                     
                    7) 
                   CCXGGGCXCAXGXCAAGXXXCAGAGAXCGG; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 8) 
                 
                 
                 
                 
               
                     
                    8) 
                   XCCACAGXXGGGCXXXXACX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 9) 
                 
                 
                 
                 
               
                     
                    9) 
                   XCXGAGAXAXAXCCACAGXX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 10) 
                 
                 
                 
                 
               
                     
                   10) 
                   XCXXGACGGGXCXGAGAXAX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 11) 
                 
                 
                 
                 
               
                     
                   11) 
                   XGAXGAGXCXCAGGAXXXGC; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 12) 
                 
                 
                 
                 
               
                     
                   12) 
                   XXCAXGGGXXXGAXGAGXCX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 13) 
                 
                 
                 
                 
               
                     
                   13) 
                   XXGXACCGXCXXXCAXGGGX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 14) 
                 
                 
                 
                 
               
                     
                   14) 
                   CAGAGAXCGGAXXCCAGXAX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 15) 
                 
                 
                 
                 
               
                     
                   15) 
                   XGXCAAGXXXCAGAGAXCGG; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 16) 
                 
                 
                 
                 
               
                     
                   16) 
                   CCXGGGCXCAXGXCAAGXXX; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 17) 
                 
                 
                 
                 
               
                     
                   17) 
                   CXGGGAAGGXXACAGCAAGA; 
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 18) 
                 
                 
                 
                 
               
                     
                   18) 
                   XCXCCXGGXCCXGGGAAGGX; 
                 
                     
                   and 
                     
                 
                     
                     
                 
                 
                 
               
                     
                   (SEQ ID NO. 19) 
                 
                 
                 
                 
               
                     
                   19) 
                   CAGCCCAXCXXCXCCXGGXC, 
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         wherein X is T or U and the oligomer's sequence can vary from the above sequence at up to two base positions, and wherein the oligomer can bind to a target site in the myostatin pre-mRNA to cause exon skipping. 
       
     
     
         2 . The oligomer of  claim 1 , wherein the oligomer causes an exon skipping rate of at least 50%. 
     
     
         3 . The oligomer of  claim 1 , wherein the oligomer causes an exon skipping rate of at least 90%. 
     
     
         4 . The oligomer of  claim 1 , wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO) or a phosphorothioate-linked 2'-O-methyl oligonucleotide (2'OMePS). 
     
     
         5 . The oligomer of  claim 1 , wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO). 
     
     
         6 . The oligomer of  claim 1 , wherein the oligomer is between 20 and 40 bases in length. 
     
     
         7 . The oligomer of  claim 1 , wherein the oligomer is about 30 bases in length. 
     
     
         8 . The oligomer of  claim 1 , wherein the base sequence is selected from the group consisting of SEQ ID NOS. 1-7. 
     
     
         9 . The oligomer of  claim 1 , wherein the base sequence is selected from the group consisting of SEQ ID NOS. 1-4. 
     
     
         10 . The oligomer of  claim 1 , wherein the oligomer comprises at least 25 contiguous bases of the base sequence selected from the group consisting of SEQ ID NOS. 1-7. 
     
     
         11 . The oligomer of  claim 1 , wherein the oligomer comprises at least 25 contiguous bases of the base sequence selected from the group consisting of SEQ ID NOS. 1-4. 
     
     
         12 . The oligomer of  claim 1 , wherein the oligomer is conjugated to or complexed with a distinct chemical entity. 
     
     
         13 . A vector for inducing exon skipping during processing of myostatin pre-mRNA, the vector encoding an oligomer of  claim 1 , wherein when the vector is introduced into a cell, the oligomer is expressed. 
     
     
         14 . A method of inducing exon skipping during processing of myostatin pre-mRNA in a patient, the method comprising administering a therapeutically effective amount of the oligomer of  claim 1  or the vector of  claim 13  to the patient such that exon skipping during processing of myostatin pre-mRNA is induced. 
     
     
         15 . The method of  claim 14 , wherein the method is for increasing or maintain muscle mass, or slowing degeneration of muscle mass in the patient. 
     
     
         16 . The method of  claim 14 , wherein the method is for ameliorating muscle wasting conditions. 
     
     
         17 . The method of  claim 14 , wherein the method is for ameliorating a muscular dystrophy such as Becker's muscular dystrophy, congenital muscular dystrophy, Duchenne muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy, myotonic muscular dystrophy and oculopharyngeal muscular dystrophy. 
     
     
         18 . The method of  claim 14 , wherein the method is for ameliorating Duchenne muscular dystrophy. 
     
     
         19 . The method of  claim 18 , wherein the method further comprises administering a therapeutically effective amount of an oligomer which causes exon skipping in the dystrophin gene and which ameliorates Duchenne muscular dystrophy.