Oligomers
Molecules are provided for inducing or facilitating exon skipping in forming spliced mRNA products from pre-mRNA molecules in cells. The molecules may be provided directly as oligonucleotides or expression products of vectors that are administered to a subject. High rates of skipping can be achieved. High rates of skipping reduce the severity of a disease like Duchene Muscular Dystrophy so that the disease is more like Becker Muscular Dystrophy. This is a severe reduction in symptom severity and mortality.
1. An oligomer for ameliorating DMD, the oligomer comprising at least 25 contiguous bases of base sequence
XGA AAA CGC CGC CAX XXC XCA ACA GAX CXG (SEQ ID NO: 1);
wherein X=U or T, wherein the oligomer's base sequence can vary from the above sequence at up to two base positions, and wherein the molecule can bind to a target site to cause exon skipping in an exon of the dystrophin gene.
2. The oligomer according to claim 1 , wherein the exon of the dystrophin gene at which exon skipping is caused is exon 44.
3. The oligomer according to claim 1 , wherein the oligomer causes an exon skipping rate of at least 50%.
4. The oligomer according to claim 1 , wherein the oligomer is between 25 and 35 bases in length.
5. The oligomer according to claim 1 , wherein the oligomer is 30 bases in length.
6. The oligomer according to claim 1 , wherein the oligomer is conjugated to or complexed with a distinct chemical entity.
7. The oligomer according to claim 1 , wherein the oligomer is a phosphorodiamidate morpholino oligonucleotide (PMO).
8. A vector for ameliorating DMD, the vector encoding an oligomer according to claim 1 , wherein when introduced into a human cell the oligomer is expressed.
9. A pharmaceutical composition for ameliorating DMD, the composition comprising an oligomer according to claim 1 or a vector according to claim 8 , and a pharmaceutically acceptable carrier, adjuvant or vehicle.
10. A pharmaceutical composition according to claim 9 comprising a plurality of oligomers or vectors encoding oligomers, or a combination of the oligomers and vectors, wherein the oligomers and/or vectors in the pharmaceutical composition cause skipping in a plurality of exons.