MULTIPLE EXON SKIPPING COMPOSITIONS FOR DMD
First Claim
Patent Images
1. A composition for use in producing skipping of exon 44 in the processing of human dystrophin pre-processed mRNA, comprisinga substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
1-20, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 44, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C.
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Abstract
Provided are antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping, and methods of use thereof to treat muscular dystrophy.
231 Citations
65 Claims
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1. A composition for use in producing skipping of exon 44 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
1-20, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 44, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (2, 3)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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4. A composition for use in producing skipping of exon 45 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
21-76 and 612 to 624, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 45, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (5, 6, 7)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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8. A composition for use in producing skipping of exon 46 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
77-125, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 46, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (9, 10, 11)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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12. A composition for use in producing skipping of exon 47 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
126-169, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 47, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (13, 14, 15)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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16. A composition for use in producing skipping of exon 48 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
170-224 and 634, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 48, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (17, 18, 19)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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20. A composition for use in producing skipping of exon 49 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
225-266, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 49, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (21, 22, 23)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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24. A composition for use in producing skipping of exon 50 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
267-308, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 50, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (25, 26, 27)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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28. A composition for use in producing skipping of exon 51 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
309-371, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 51, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (29, 30, 31)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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32. A composition for use in producing skipping of exon 52 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
372-415, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 52, a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (33, 34, 35)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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36. A composition for use in producing skipping of exon 53 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
416-475 and 625-633, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 53 a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (37, 38, 39)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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40. A composition for use in producing skipping of exon 54 in the processing of human dystrophin pre-processed mRNA, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
476-519, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 54 a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (41, 42, 43)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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44. A composition for use in producing skipping of exon 55 in the processing of human dystrophin-gene pre-processed mRNA transcript, comprising
a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ - exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
520-569 and 635, and capable of forming with the complementary mRNA sequence in the dystrophin-gene exon 55 a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C. - View Dependent Claims (45, 46, 47)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
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48. A method of treating muscular dystrophy in a subject, comprising administering to the subject an effective amount of a substantially uncharged antisense compound containing 20-35 morpholino subunits linked by phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
1 to 569 and 612 to 635, and capable of forming with the complementary mRNA sequence in a dystrophin-gene exon a heteroduplex structure between said compound and mRNA having a Tm of at least 45°
C., wherein the exon is selected from the group consisting of exons 44-55. - View Dependent Claims (49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65)
- exocyclic carbon of an adjacent subunit, comprising a sequence selected from the group consisting SEQ ID NOS;
Specification