Methods and materials for activating an internal ribosome entry site in exon 5 of the dmd gene

Abstract

The present invention relates to the delivery of oligomers for treating patients with a 5′ mutation in their DMD gene other than a DMD exon 2 duplication. The invention provides methods and materials for activating an internal ribosome entry site in exon 5 of the DMD gene resulting in translation of a functional truncated isoform of dystrophin. The methods and materials can be used for the treatment of muscular dystrophies arising from 5′ mutations in the DMD gene such as Duchenne Muscular Dystrophy or Becker Muscular Dystrophy.

1 - 23 . (canceled) 
     
     
         24 . A method of ameliorating Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in a patient with a 5′ mutation in a DMD gene but without a DMD exon 2 duplication, the method comprising administering to the patient a recombinant adeno-associated virus (rAAV) comprising a DMD exon 5 internal ribosome entry site (IRES)-activating oligomer construct comprising:
 (a) the nucleotide sequence set forth in SEQ ID NO: 5, 7, or 8; or 
 (b) a nucleotide sequence that expresses an RNA transcript comprising the nucleotide sequence set forth in SEQ ID NO: 9, 11, or 12. 
 
     
     
         25 . The method of  claim 24 , wherein the progression of a dystrophic pathology is inhibited in the patient following administration of the rAAV to the patient. 
     
     
         26 . The method of  claim 24 , wherein muscle function is improved in the patient following administration of the rAAV to the patient. 
     
     
         27 . The method of  claim 26 , wherein the improvement in muscle function is an improvement in muscle strength or an improvement in stability in standing and walking. 
     
     
         28 . The method of  claim 24 , wherein the genome of the rAAV lacks adeno-associated virus rep and cap DNA. 
     
     
         29 . The method of  claim 24 , wherein the genome of the rAAV is a self-complementary genome. 
     
     
         30 . The method of  claim 24 , wherein the genome of the rAAV is a single-stranded genome. 
     
     
         31 . The method of  claim 24 , wherein the rAAV comprises one or more capsid proteins from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, or AAVrh74. 
     
     
         32 . The method of  claim 31 , wherein the rAAV comprises one or more capsid proteins from AAV1, AAV6, AAV8, AAV9, or AAVrh74. 
     
     
         33 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises the nucleotide sequence set forth in SEQ ID NO: 5. 
     
     
         34 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises the nucleotide sequence set forth in SEQ ID NO: 7. 
     
     
         35 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises the nucleotide sequence set forth in SEQ ID NO: 8. 
     
     
         36 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises a nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 9. 
     
     
         37 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises a nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 11. 
     
     
         38 . The method of  claim 24 , wherein the DMD exon 5 IRES-activating oligomer construct comprises a nucleotide sequence that expresses an RNA comprising the nucleotide sequence set forth in SEQ ID NO: 12. 
     
     
         39 . The method of  claim 24 , further comprising administering a glucocorticoid to the patient.