Combined therapy for duchenne muscular dystrophy
The present invention relates to the combined use of antisense oligonucleotides and viral vectors for the treatment of Duchenne muscular dystrophy.
1. A combination therapy method comprising:
administering to a human subject an isolated antisense oligonucleotide (AON) between 10 and 40 nucleotides in length capable of inducing an exon-skipping in a dystrophin pre-mRNA thereby inducing functional dystrophin expression, and
subsequently administering to the subject at least one viral vector encoding a Duchenne muscular dystrophy therapeutic product selected from (i) an antisense oligonucleotide able to induce exon-skipping within a dystrophin pre-mRNA, (ii) a dystrophin gene-editing endonuclease, and (iii) a functional dystrophin protein;
wherein the pretreatment with the AON prevents the loss of therapeutic viral vector genomes from the muscles of the subject.
2. The method of claim 1 , wherein said AON is administered as a pretreatment 1-40 days before administration of the viral vector.
3. The method of claim 1 , wherein the viral vector is an AAV vector.
4. The method of claim 1 , wherein said AON is a phosphorodiamidate morpholino oligomer.
5. The method of claim 1 , wherein said AON is a peptide-phosphorodiamidate morpholino oligomer.
6. The method of claim 1 , wherein said AON is a Pip6a-PMO oligomer.
7. The method of claim 1 , wherein said viral vector encodes an U7-AON.
8. The method of claim 1 , wherein said viral vector encodes a functional truncated dystrophin.
9. The method of claim 1 , wherein said AON is administered as a pretreatment 12-16 days before administration of the viral vector.
10. The method of claim 1 , wherein said AON is administered as a pretreatment 14-28 days before administration of the viral vector.
11. The method of claim 1 , wherein said AON is administered as a pretreatment at least one week before administration of the viral vector.
12. The method of claim 1 , wherein said AON is administered as a pretreatment at least two weeks before administration of the viral vector.
13. The method of claim 1 , wherein said AON is between 15 and 40, or 20 and 40, or 25 and 40 nucleotides in length.