IT 1S CLAIMED:
`
`CLAIMS
`
`4140.001000E
`
`1.A composition for use in producing skipping of exon 44 in the
`
`processing of human dystrephin 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.
`
`2. The composition of claim 1, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 8, 11 and 12.
`
`3. The composition of claim 1, wherein the compoundis conjugated to an
`
`arginine-rich) peptide having a sequence selected from the group consisting cf SEQ ID
`
`NOS: 570-578.
`
`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.
`
`110
`
`
`
`CLAIMS
`
`4140.001000E
`
`1.A composition for use in producing skipping of exon 44 in the
`
`processing of human dystrephin 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.
`
`2. The composition of claim 1, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 8, 11 and 12.
`
`3. The composition of claim 1, wherein the compoundis conjugated to an
`
`arginine-rich) peptide having a sequence selected from the group consisting cf SEQ ID
`
`NOS: 570-578.
`
`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.
`
`110
`
`
`
`5. The composition of claim 4, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 27, 29, 34 and 39.
`
`4140.001000E
`
`6. The composition of claim 5, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 29 and 34.
`
`7, The composition of claim 4, wherein the compoundis conjugated to an
`
`arginine-richt peptide having a sequence selected from the group consisting of SEQ ID
`
`NOS: 570-578.
`
`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.
`
`9. The composition of claim 8, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 77-105.
`
`10.
`
`The composition of claim 9, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 82, 84-87, 90, 96, 98, 99
`
`and 101.
`
`111
`
`
`
`11.
`
`The composition of claim 8, wherein the compound is conjugated to
`
`an arginine-rich peptide having a sequence selected from the group consisting of SEQ
`
`4140.001000E
`
`ID NOS: 570-578.
`
`12.
`
`A composition for use in preducing 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.
`
`13.
`
`The composition of claim 12, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 126-149.
`
`14.
`
`The composition of claim 13, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ iD NOS: 126, 128-130, 132, 144
`
`and 146-149.
`
`15.
`
`The composition of claim 12, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`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
`
`112
`
`
`
`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 cf 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.
`
`4140.001000E
`
`17.
`
`The composition of claim 16, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 170-201 and 634.
`
`18.
`
`|The composition of claim 17, wherein the compound contains a
`
`sequence selected fram the group consisting of SEQ ID NOS: 176, 178, 181-183, 194
`
`and 198-201.
`
`19.
`
`The composition of claim 16, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`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
`
`cempound
`
`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 mRNAhaving a Tm of
`
`at least 45°C.
`
`21.
`
`The composition of claim 20, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 225-248.
`
`113
`
`
`
`22.
`
`the composition of claim 21, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 227, 229, 234, 236, 237
`
`4140.001000E
`
`and 244-248.
`
`23.
`
`The composition of claim 20, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ !D NOS: 570-578.
`
`24.
`
`A composition for use in producing skipping of exon 50 in the
`
`processing of human dystrephin pre-processed mRNA, comprising
`
`a_
`
`substantially uncharged
`
`antisense
`
`compound
`
`containing
`
`20-35
`
`morpholino subunits linked by phosphorus-containing intersubunit
`
`linkages joining a
`
`morpholino nitrogen cf 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.
`
`25.
`
`The composition of claim 24, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 277, 287, 290 and 291.
`
`26.
`
`The composition of claim 25, wherein the compound contains the
`
`sequenceconsisting of SEQ ID NO: 287.
`
`27.
`
`The camposition of claim 24, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ !D NOS: 570-578.
`
`114
`
`
`
`4140.001000E
`
`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.
`
`29.
`
`The composition of claim 28, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 324, 326 and 327.
`
`30.
`
`The composition of claim 29, wherein the compound contains the
`
`sequenceconsisting of SEQ ID NO: 327.
`
`31.
`
`The composition of claim 28, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`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.
`
`115
`
`
`
`33.
`
`The composition of claim 32, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 372-397.
`
`4140.001000E
`
`34.
`
`The composition of claim 33, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 379-382, 384, 390 and
`
`392-395.
`
`35.|The composition of claim 32, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ 1D NOS: 570-578.
`
`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
`
`morpholine subunits linked by phespherus-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.
`
`37.
`
`The composition of claim 36, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 428, 429 and 437%.
`
`38.
`
`The composition of claim 37, wherein the compound contains a
`
`sequenceconsisting of SEQ ID NO: 429.
`
`116
`
`
`
`39.
`
`The composition of claim 36, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`4140.001000E
`
`40.
`
`A composition for use in praducing 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.
`
`41.
`
`|The composition of claim 40, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 476-499.
`
`42.
`
`The composition of claim 41, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 479-482, 484, 489 and
`
`491-493.
`
`43.|The composition of claim 40, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`44.
`
`A composition for use in producing skipping of exon 55 in the
`
`processing of human dystrophin-gene pre-precessed mRNAtranscript, comprising
`
`a_
`
`substantially uncharged
`
`antisense
`
`compound
`
`containing
`
`20-35
`
`morpholino subunits linked by phosphorus-containing intersubunit
`
`linkages joining a
`
`117
`
`
`
`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 cf 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.
`
`4140.001000E
`
`45.
`
`The composition of claim 44, wherein the compound contains a
`
`sequenceselected from the group consisting of SEQ ID NOS: 520-546 and 635.
`
`46.
`
`The composition of claim 45, wherein the compound contains a
`
`sequence selected from the group consisting of SEQ ID NOS: 524-528, 537, 539, 540,
`
`542 and 544.
`
`47,
`
`The composition of claim 44, wherein the compound is conjugated
`
`to an arginine-rich peptide having a sequence selected from the group consisting of
`
`SEQ ID NOS: 570-578.
`
`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 phesphorus-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 mRNAhaving a Tm of at least 45°C, wherein the exonis
`
`selected from the group consisting of exons 44-55.
`
`49.
`
`The method of claim 48, wherein the muscular dystrophy is
`
`Duchenne’s muscular dystrophy (DMD}.
`
`118
`
`
`
`50.
`
`The method of claim 48, wherein the muscular dystrophy is Becker
`
`4140.001000E
`
`muscular dystrophy (BMD),
`
`51.
`
`The methad cf claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 1-20, and the exon is exon 44.
`
`52.
`
`The method of claim 48, wherein the sequence is selected fram the
`
`group consisting SEQ ID NOS: 21-76 and 612 to 624, and the exon is exon 45.
`
`53.
`
`The method of claim 48, wherein the sequenceis selected from the
`
`group consisting SEQ ID NOS: 77-125, and the exon is exon 46.
`
`54.
`
`The method of claim 48, wherein the sequence selected from the
`
`group consisting SEQ ID NOS: 4126-169, and the exon is exon 47.
`
`55.
`
`The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 470-224 and 634, and the exon is exon 48.
`
`56.
`
`The method of claim 48, wherein the sequence selected from the
`
`group consisting SEQ ID NOS: 225-266, and the exon is exon 49.
`
`57.
`
`Fre method of claim 48, wherein the sequence is selected fram the
`
`group consisting SEQ ID NOS: 267-308, and the exon is exon 50.
`
`58.
`
`The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 309-371, and the exon is exon 54.
`
`59.
`
`The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 372-415, and the exon is exon 52.
`
`119
`
`
`
`60.
`
`The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 416-475 and 625-633, and the exon is exon 53.
`
`4140.001000E
`
`64.
`
`The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 476-519, and the exon is exen 54.
`
`62.
`
`|The method of claim 48, wherein the sequence is selected from the
`
`group consisting SEQ ID NOS: 520-569 and 635, and the exon is exon 55.
`
`63.
`
`|The method of claim 48, wherein the sequence comprises SEQ ID
`
`NO:287.
`
`64.
`
`The method of claim 48, wherein the compound is conjugated to an
`
`arginine-rich peptide.
`
`65.
`
`The method of claim 64, wherein the arginine-rich peptide
`
`comprises a sequence selected from the group consisting of SEQ ID NOS: 570-578.
`
`120
`
`
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