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 a base sequence selected from the group consisting of:
(SEQ ID NO: 6)
a) XGC XGC XCX XXX CCA GGX XCA AGX GGG AXA;
(SEQ ID NO: 7)
b) CXX XXA GXX GCX GCX CXX XXC CAG GXX CAA;
(SEQ ID NO: 8)
c) CXX XXC XXX XAG XXG CXG CXC XXX XCC AGG;
and
(SEQ ID NO: 9)
d) XXA GXX GCX GCX CXX XXC CAG GXX CAA GXG;
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 exon 46.
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 30 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.
11. The oligomer according to claim 1 , wherein the oligomer comprises SEQ ID NO: 6.
12. The oligomer according to claim 1 , wherein the oligomer comprises SEQ ID NO: 7.
13. The oligomer according to claim 1 , wherein the oligomer comprises SEQ ID NO: 8.
14. The oligomer according to claim 1 , wherein the oligomer comprises SEQ ID NO: 9.