Oligonucleotide comprising an inosine for treating DMD

Abstract

The invention provides an oligonucleotide comprising an inosine, and/or a nucleotide containing a base able to form a wobble base pair or a functional equivalent thereof, wherein the oligonucleotide, or a functional equivalent thereof, comprises a sequence which is complementary to at least part of a dystrophin pre-m RNA exon or at least part of a non-exon region of a dystrophin pre-m RNA said part being a contiguous stretch comprising at least 8 nucleotides. The invention further provides the use of said oligonucleotide for preventing or treating DMD or BMD.

Claims

1. An oligonucleotide consisting of the base sequence of any one of SEQ ID NO: 141, 142 or 144-188, wherein at least one guanosine base in the sequence is substituted with an inosine base, and wherein said oligonucleotide comprises a modification and induces skipping of exon 53 of human dystrophin pre-mRNA.

2. The oligonucleotide of claim 1, wherein one to four guanosine bases in the sequence are substituted with an inosine base.

3. The oligonucleotide of claim 1, wherein the modification is a base and/or sugar modification.

4. The oligonucleotide of claim 3, wherein the oligonucleotide is a 2′-O-methyl phosphorothioate oligonucleotide.

5. The oligonucleotide of claim 3, wherein the oligonucleotide is a peptide nucleic acid.

6. The oligonucleotide of claim 3, wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer.

7. A pharmaceutical composition, comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.

8. A method for inducing skipping of exon 53 of human dystrophin pre-mRNA in a human subject, comprising administering the oligonucleotide of claim 1 to the human subject in an amount and for a time which is effective to induce exon skipping.

9. A method for alleviating one or more symptom(s) of Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in a human subject, comprising administering to the human subject the oligonucleotide of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1. In human control myotubes, PS220 and PS305 both targeting an identical sequence within exon 45, were directly compared for relative skipping efficiencies. PS220 reproducibly induced highest levels of exon 45 skipping (up to 73%), whereas with PS305 maximum exon 45 skipping levels of up to 46% were obtained. No exon 45 skipping was observed in non-treated cells. (M: DNA size marker; NT: non-treated cells)

(2) FIG. 2. Graph showing relative exon 45 skipping levels of inosine-containing AONs as assessed by RT-PCR analysis. In human control myotubes, a series of new AONs, all targeting exon 45 and containing one inosine for guanosine substitution were tested for relative exon 45 skipping efficiencies when compared with PS220 and PS305 (see FIG. 1). All new inosine-containing AONs were effective, albeit at variable levels (between 4% and 25%). PS220 induced highest levels of exon 45 skipping (up to 72%), whereas with PS305 maximum exon 45 skipping levels of up to 63% were obtained. No exon 45 skipping was observed in non-treated cells. (M: DNA size marker; NT: non-treated cells).

EXAMPLES

Example 1

(3) Materials and Methods

(4) AON design was based on (partly) overlapping open secondary structures of the target exon RNA as predicted by the m-fold program, on (partly) overlapping putative SR-protein binding sites as predicted by the ESE-finder software. AONs were synthesized by Prosensa Therapeutics B.V. (Leiden, Netherlands), and contain 2′-O-methyl RNA and full-length phosphorothioate (PS) backbones.

(5) Tissue Culturing, Transfection and RT-PCR Analysis

(6) Myotube cultures derived from a healthy individual (“human control”) (examples 1, 3, and 4; exon 43, 50, 52 skipping) or a DMD patient carrying an exon 45 deletion (example 2; exon 46 skipping) were processed as described previously (Aartsma-Rus et al., Neuromuscul. Disord. 2002; 12: S71-77 and Hum Mol Genet 2003; 12(8): 907-14). For the screening of AONs, myotube cultures were transfected with 200 nM for each AON (PS220 and PS305). Transfection reagent UNIFectylin (Prosensa Therapeutics BV, Netherlands) was used, with 2 μl UNIFectylin per μg AON. Exon skipping efficiencies were determined by nested RT-PCR analysis using primers in the exons flanking the targeted exon 45. PCR fragments were isolated from agarose gels for sequence verification. For quantification, the PCR products were analyzed using the DNA 1000 LabChip Kit on the Agilent 2100 bioanalyzer (Agilent Technologies, USA).

(7) Results

(8) DMD Exon 45 Skipping.

(9) Two AONs, PS220 (SEQ ID NO: 76; 5′-UUUGCCGCUGCCCAAUGCCAUCCUG-3′) and PS305 (SEQ ID NO: 557; 5′-UUUGCCICUGCCCAAUGCCAUCCUG-3′) both targeting an identical sequence within exon 45, were directly compared for relative skipping efficiencies in healthy control myotube cultures. Subsequent RT-PCR and sequence analysis of isolated RNA demonstrated that both AONs were indeed capable of inducing exon 45 skipping. PS220, consisting a GCCGC stretch, reproducibly induced highest levels of exon 45 skipping (up to 73%), as shown in FIG. 1. However, PS305, which is identical to PS220 but containing an inosine for a G substitution at position 4 within that stretch is also effective and leading to exon 45 skipping levels of up to 46%. No exon 45 skipping was observed in non-treated cells (NT).

Example 2

(10) Materials and Methods

(11) AON design was based on (partly) overlapping open secondary structures of the target exon 45 RNA as predicted by the m-fold program, on (partly) overlapping putative SR-protein binding sites as predicted by the ESE-finder software. AONs were synthesized by Prosensa Therapeutics B.V. (Leiden, Netherlands), and contain 2′-O-methyl RNA, full-length phosphorothioate (PS) backbones and one inosine for guanosine substitution.

(12) Tissue Culturing, Transfection and RT-PCR Analysis

(13) Myotube cultures derived from a healthy individual (“human control”) were processed as described previously (Aartsma-Rus et al., Neuromuscul. Disord. 2002; 12: S71-77 and Hum Mol Genet 2003; 12(8): 907-14). For the screening of AONs, myotube cultures were transfected with 200 nM for each AON. Transfection reagent UNIFectylin (Prosensa Therapeutics BV, Netherlands) was used, with 2 μl UNIFectylin per μg AON. Exon skipping efficiencies were determined by nested RT-PCR analysis using primers in the exons flanking the targeted exon 45. PCR fragments were isolated from agarose gels for sequence verification. For quantification, the PCR products were analyzed using the DNA 1000 Lab Chip Kit on the Agilent 2100 bioanalyzer (Agilent Technologies, USA).

(14) Results

(15) DMD Exon 45 Skipping.

(16) An additional series of AONs targeting exon 45 and containing one inosine-substitution were tested in healthy control myotube cultures for exon 45 skipping efficiencies, and directly compared to PS220 (without inosine; SEQ ID NO: 76)) and PS305 (identical sequence as PS220 but with inosine substitution; SEQ ID NO: 557). Subsequent RT-PCR and sequence analysis of isolated RNA demonstrated that all new AONs (PS309 to PS316) were capable of inducing exon 45 skipping between 4% (PS311) and 25% (PS310) as shown in FIG. 2. When compared to PS220 and PS305, PS220 induced highest levels of exon 45 skipping (up to 72%). Of the new inosine-containing AONs PS305 was most effective, showing exon 45 skipping levels of up to 63%. No exon 45 skipping was observed in non-treated cells (NT).

REFERENCES

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(20) TABLE-US-00001 Sequence listing DMD gene amino acid sequence SEQ ID NO 1: MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGL TCQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIIL HWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFITSWSDGLALNALIH SHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYIT SLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSP KPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEV LSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGT GKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLT KTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSG DHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKE DAVNKIHTTGFKDQNEMLSSLQKLAVLKADLEKKKQSMGKLYSLKQDLLSTLKNKSVT QKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILV KHAQEELPPPPPQKKRQITVDSEIRKRLDVDITELHSWITRSEAVLQSPEFAIFRKEGNF SDLKEKVNAIEREKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIE FCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKIC KDEVNRLSGLQPQIERLKIQSIALKEKGQGPMFLDADFVAFTNHFKQVFSDVQAREKEL QTIFDTLPPMRYQETMSAIRTWVQQSETKLSIPQLSVTDYEIMEQRLGELQALQSSLQE QQSGLYYLSTTVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNK LRKIQNHIQTLKKWMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSV NEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKD LSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESV NSVIAQAPPVAQEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACWHELLSYLEKAN KWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMD ELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYI ADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVS MKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLS EVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLK LSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVH LKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFD QNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMA NRGDHCRKLVE PQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQ GVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNA LKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDREL QKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTV REETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQE ESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKD RQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGI CQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKN ILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGILKQL NETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKK LEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVQETEIAVQAKQPDVEEILSKGQH LYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGASPTQTVTLVTQ PVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDI NEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQ EHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITE TKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSER EAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQ WQDLQGEIEAHTDVYHNLDENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSL NIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFK RELKTKEPVIMSTLETVRIFLTEQPLEGLEKLYQEPRELPPEERAQNVTRLLRKQAEEV NTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLID SLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQ VAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHP KMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQ PMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTG IISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSV RSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPI IGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNK FRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRI EHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILIS LESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRD AELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSS PSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRG RNTPGKPMREDTM DMD Gene Exon 51 SEQ ID GUACCUCCAACAUCAAGGAAGAUGG SEQ ID GAGAUGGCAGUUUCCUUAGUAACCA NO 2 NO 39 SEQ ID UACCUCCAACAUCAAGGAAGAUGGC SEQ ID AGAUGGCAGUUUCCUUAGUAACCAC NO 3 NO 40 SEQ ID ACCUCCAACAUCAAGGAAGAUGGCA SEQ ID GAUGGCAGUUUCCUUAGUAACCACA NO 4 NO 41 SEQ ID CCUCCAACAUCAAGGAAGAUGGCAU SEQ ID AUGGCAGUUUCCUUAGUAACCACAG NO 5 NO 42 SEQ ID CUCCAACAUCAAGGAAGAUGGCAUU SEQ ID UGGCAGUUUCCUUAGUAACCACAGG NO 6 NO 43 SEQ ID UCCAACAUCAAGGAAGAUGGCAUUU SEQ ID GGCAGUUUCCUUAGUAACCACAGGU NO 7 NO 44 SEQ ID CCAACAUCAAGGAAGAUGGCAUUUC SEQ ID GCAGUUUCCUUAGUAACCACAGGUU NO 8 NO 45 SEQ ID CAACAUCAAGGAAGAUGGCAUUUCU SEQ ID CAGUUUCCUUAGUAACCACAGGUUG NO 9 NO 46 SEQ ID AACAUCAAGGAAGAUGGCAUUUCUA SEQ ID AGUUUCCUUAGUAACCACAGGUUGU NO 10 NO 47 SEQ ID ACAUCAAGGAAGAUGGCAUUUCUAG SEQ ID GUUUCCUUAGUAACCACAGGUUGUG NO 11 NO 48 SEQ ID CAUCAAGGAAGAUGGCAUUUCUAGU SEQ ID UUUCCUUAGUAACCACAGGUUGUGU NO 12 NO 49 SEQ ID AUCAAGGAAGAUGGCAUUUCUAGUU SEQ ID UUCCUUAGUAACCACAGGUUGUGUC NO 13 NO 50 SEQ ID UCAAGGAAGAUGGCAUUUCUAGUUU SEQ ID UCCUUAGUAACCACAGGUUGUGUCA NO 14 NO 51 SEQ ID CAAGGAAGAUGGCAUUUCUAGUUUG SEQ ID CCUUAGUAACCACAGGUUGUGUCAC NO 15 NO 52 SEQ ID AAGGAAGAUGGCAUUUCUAGUUUGG SEQ ID CUUAGUAACCACAGGUUGUGUCACC NO 16 NO 53 SEQ ID AGGAAGAUGGCAUUUCUAGUUUGGA SEQ ID UUAGUAACCACAGGUUGUGUCACCA NO 17 NO 54 SEQ ID GGAAGAUGGCAUUUCUAGUUUGGAG SEQTD UAGUAACCACAGGUUGUGUCACCAG NO 18 NO 55 SEQ ID GAAGAUGGCAUUUCUAGUUUGGAGA SEQ ID AGUAACCACAGGUUGUGUCACCAGA NO 19 NO 56 SEQ ID AAGAUGGCAUUUCUAGUUUGGAGAU SEQ ID GUAACCACAGGUUGUGUCACCAGAG NO 20 NO 57 SEQ ID AGAUGGCAUUUCUAGUUUGGAGAUG SEQ ID UAACCACAGGUUGUGUCACCAGAGU NO 21 NO 58 SEQ ID GAUGGCAUUUCUAGUUUGGAGAUGG SEQ ID AACCACAGGUUGUGUCACCAGAGUA NO 22 NO 59 SEQ ID AUGGCAUUUCUAGUUUGGAGAUGGC SEQ ID ACCACAGGUUGUGUCACCAGAGUAA NO 23 NO 60 SEQ ID UGGCAUUUCUAGUUUGGAGAUGGCA SEQ ID CCACAGGUUGUGUCACCAGAGUAAC NO 24 NO 61 SEQ ID GGCAUUUCUAGUUUGGAGAUGGCAG SEQ ID CACAGGUUGUGUCACCAGAGUAACA NO 25 NO 62 SEQ ID GCAUUUCUAGUUUGGAGAUGGCAGU SEQ ID ACAGGUUGUGUCACCAGAGUAACAG NO 26 NO 63 SEQ ID CAUUUCUAGUUUGGAGAUGGCAGUU SEQ ID CAGGUUGUGUCACCAGAGUAACAGU NO 27 NO 64 SEQ ID AUUUCUAGUUUGGAGAUGGCAGUUU SEQ ID AGGUUGUGUCACCAGAGUAACAGUC NO 28 NO 65 SEQ ID UUUCUAGUUUGGAGAUGGCAGUUUC SEQ ID GGUUGUGUCACCAGAGUAACAGUCU NO 29 NO 66 SEQ ID UUCUAGUUUGGAGAUGGCAGUUUCC SEQ ID GUUGUGUCACCAGAGUAACAGUCUG NO 30 NO 67 SEQ ID UCUAGUUUGGAGAUGGCAGUUUCCU SEQ ID UUGUGUCACCAGAGUAACAGUCUGA NO 31 NO 68 SEQ ID CUAGUUUGGAGAUGGCAGUUUCCUU SEQ ID UGUGUCACCAGAGUAACAGUCUGAG NO 32 NO 69 SEQ ID UAGUUUGGAGAUGGCAGUUUCCUUA SEQ ID GUGUCACCAGAGUAACAGUCUGAGU NO 33 NO 70 SEQ ID AGUUUGGAGAUGGCAGUUUCCUUAG SEQ ID UGUCACCAGAGUAACAGUCUGAGUA NO 34 NO 71 SEQ ID GUUUGGAGAUGGCAGUUUCCUUAGU SEQ ID GUCACCAGAGUAACAGUCUGAGUAG NO 35 NO 72 SEQ ID UUUGGAGAUGGCAGUUUCCUUAGUA SEQ ID UCACCAGAGUAACAGUCUGAGUAGG NO 36 NO 73 SEQ ID UUGGAGAUGGCAGUUUCCUUAGUAA SEQ ID CACCAGAGUAACAGUCUGAGUAGGA NO 37 NO 74 SEQ ID UGGAGAUGGCAGUUUCCUUAGUAAC SEQ ID ACCAGAGUAACAGUCUGAGUAGGAG NO 38 NO 75 SEQ ID UCAAGGAAGAUGGCAUUUCU SEQ ID UCAAGGAAGAUGGCAUIUCU NO 539 NO 548 SEQ ID UCAAIGAAGAUGGCAUUUCU SEQ ID UCAAGGAAGAUGGCAUUICU NO 540 NO 549 SEQ ID UCAAGIAAGAUGGCAUUUCU SEQ ID UCAAGGAAGAUGGCAUUUCI NO 541 NO 550 SEQ ID UCAAGGAAIAUGGCAUUUCU SEQ ID UCIAGGAAGAUGGCAUUUCU NO 542 NO 551 SEQ ID UCAAGGAAGAUIGCAUUUCU SEQ ID UCAIGGAAGAUGGCAUUUCU NO 543 NO 552 SEQ ID UCAAGGAAGAUGICAUUUCU SEQ ID UCAAGGIAGAUGGCAUUUCU NO 544 NO 553 SEQ ID ICAAGGAAGAUGGCAUUUCU SEQ ID UCAAGGAIGAUGGCAUUUCU NO 545 NO 554 SEQ ID UCAAGGAAGAIGGCAUUUCU SEQ ID UCAAGGAAGIUGGCAUUUCU NO 546 NO 555 SEQ ID UCAAGGAAGAUGGCAIUUCU SEQ ID UCAAGGAAGAUGGCIUUUCU NO 547 NO 556 DMD Gene Exon 45 SEQ ID UUUGCCGCUGCCCAAUGCCAUCCUG SEQ ID GUUGCAUUCAAUGUUCUGACAACAG NO 76 NO 109 PS220 SEQ ID AUUCAAUGUUCUGACAACAGUUUGC SEQ ID UUGCAUUCAAUGUUCUGACAACAGU NO 77 NO 110 SEQ ID CCAGUUGCAUUCAAUGUUCUGACAA SEQ ID UGCAUUCAAUGUUCUGACAACAGUU NO 78 NO 111 SEQ ID CAGUUGCAUUCAAUGUUCUGAC SEQ ID GCAUUCAAUGUUCUGACAACAGUUU NO 79 NO 112 SEQ ID AGUUGCAUUCAAUGUUCUGA SEQ ID CAUUCAAUGUUCUGACAACAGUUUG NO 80 NO 113 SEQ ID GAUUGCUGAAUUAUUUCUUCC SEQ ID AUUCAAUGUUCUGACAACAGUUUGC NO 81 NO 114 SEQ ID GAUUGCUGAAUUAUUUCUUCCCCAG SEQ ID UCAAUGUUCUGACAACAGUUUGCCG NO 82 NO 115 SEQ ID AUUGCUGAAUUAUUUCUUCCCCAGU SEQ ID CAAUGUUCUGACAACAGUUUGCCGC NO 83 NO 116 SEQ ID UUGCUGAAUUAUUUCUUCCCCAGUU SEQ ID AAUGUUCUGACAACAGUUUGCCGCU NO 84 NO 117 SEQ ID UGCUGAAUUAUUUCUUCCCCAGUUG SEQ ID AUGUUCUGACAACAGUUUGCCGCUG NO 85 NO 118 SEQ ID GCUGAAUUAUUUCUUCCCCAGUUGC SEQ ID UGUUCUGACAACAGUUUGCCGCUGC NO 86 NO 119 SEQ ID CUGAAUUAUUUCUUCCCCAGUUGCA SEQ ID GUUCUGACAACAGUUUGCCGCUGCC NO 87 NO 120 SEQ ID UGAAUUAUUUCUUCCCCAGUUGCAU SEQ ID UUCUGACAACAGUUUGCCGCUGCCC NO 88 NO 121 SEQ ID GAAUUAUUUCUUCCCCAGUUGCAUU SEQ ID UCUGACAACAGUUUGCCGCUGCCCA NO 89 NO 122 SEQ ID AAUUAUUUCUUCCCCAGUUGCAUUC SEQ ID CUGACAACAGUUUGCCGCUGCCCAA NO 90 NO 123 SEQ ID AUUAUUUCUUCCCCAGUUGCAUUCA SEQ ID UGACAACAGUUUGCCGCUGCCCAAU NO 91 NO 124 SEQ ID UUAUUUCUUCCCCAGUUGCAUUCAA SEQ ID GACAACAGUUUGCCGCUGCCCAAUG NO 92 NO 125 SEQ ID UAUUUCUUCCCCAGUUGCAUUCAAU SEQ ID ACAACAGUUUGCCGCUGCCCAAUGC NO 93 NO 126 SEQ ID AUUUCUUCCCCAGUUGCAUUCAAUG SEQ ID CAACAGUUUGCCGCUGCCCAAUGCC NO 94 NO 127 SEQ ID UUUCUUCCCCAGUUGCAUUCAAUGU SEQ ID AACAGUUUGCCGCUGCCCAAUGCCA NO 95 NO 128 SEQ ID UUCUUCCCCAGUUGCAUUCAAUGUU SEQ ID ACAGUUUGCCGCUGCCCAAUGCCAU NO 96 NO 129 SEQ ID UCUUCCCCAGUUGCAUUCAAUGUUC SEQ ID CAGUUUGCCGCUGCCCAAUGCCAUC NO 97 NO 130 SEQ ID CUUCCCCAGUUGCAUUCAAUGUUCU SEQ ID AGUUUGCCGCUGCCCAAUGCCAUCC NO 98 NO 131 SEQ ID UUCCCCAGUUGCAUUCAAUGUUCUG SEQ ID GUUUGCCGCUGCCCAAUGCCAUCCU NO 99 NO 132 SEQ ID UCCCCAGUUGCAUUCAAUGUUCUGA SEQ ID UUUGCCGCUGCCCAAUGCCAUCCUG NO 100 NO 133 SEQ ID CCCCAGUUGCAUUCAAUGUUCUGAC SEQ ID UUGCCGCUGCCCAAUGCCAUCCUGG NO 101 NO 134 SEQ ID CCCAGUUGCAUUCAAUGUUCUGACA SEQ ID UGCCGCUGCCCAAUGCCAUCCUGGA NO 102 NO 135 SEQ ID CCAGUUGCAUUCAAUGUUCUGACAA SEQ ID GCCGCUGCCCAAUGCCAUCCUGGAG NO 103 NO 136 SEQ ID CAGUUGCAUUCAAUGUUCUGACAAC SEQ ID CCGCUGCCCAAUGCCAUCCUGGAGU NO 104 NO 137 SEQ ID AGUUGCAUUCAAUGUUCUGACAACA SEQ ID CGCUGCCCAAUGCCAUCCUGGAGUU NO 105 NO 138 SEQ ID UCC UGU AGA AUA CUG GCA UC SEQ ID UGUUUUUGAGGAUUGCUGAA NO 106 NO 139 SEQ ID UGCAGACCUCCUGCCACCGCAGAUU SEQ ID UGUUCUGACAACAGUUUGCCGCUGCC NO 107 CA NO 140 CAAUGCCAUCCUGG SEQ ID UUGCAGACCUCCUGCCACCGCAGAU SEQ ID UUUGCCICUGCCCAAUGCCAUCCUG NO 108 UCAGGCUUC NO 557 PS305 SEQ ID UUUGCCGCUICCCAAUGCCAUCCUG SEQ ID UUUGCCGCUGCCCAIUGCCAUCCUG NO 558 NO 566 SEQ ID UUUGCCGCUGCCCAAUICCAUCCUG SEQ ID UUUGCCGCUGCCCAAUGCCIUCCUG NO 559 NO 567 SEQ ID UUUICCGCUGCCCAAUGCCAUCCUG SEQ ID UUUICCICUGCCCAAUGCCAUCCUG NO 560 NO 568 SEQ ID UUUGCCGCUGCCCAAUGCCAUCCUI SEQ ID UUUGCCGCUGCCCAAIGCCAUCCUG NO 561 NO 569 SEQ ID IUUGCCGCUGCCCAAUGCCAUCCUG SEQ ID UUUGCCGCUGCCCAAUGCCAICCUG NO 562 NO 570 SEQ ID UIUGCCGCUGCCCAAUGCCAUCCUG SEQ ID UUUGCCGCUGCCCAAUGCCAUCCIG NO 563 NO 571 SEQ ID UUIGCCGCUGCCCAAUGCCAUCCUG SEQ ID UUUGCCGCUGCCCIAUGCCAUCCUG NO 564 NO 572 SEQ ID UUUGCCGCIGCCCAAUGCCAUCCUG NO 565 DMD Gene Exon 53 SEQ ID CUCUGGCCUGUCCUAAGACCUGCUC SEQ ID CAGCUUCUUCCUUAGCUUCCAGCCA NO 141 NO 165 SEQ ID UCUGGCCUGUCCUAAGACCUGCUCA SEQ ID AGCUUCUUCCUUAGCUUCCAGCCAU NO 142 NO 166 SEQ ID CUGGCCUGUCCUAAGACCUGCUCAG SEQ ID GCUUCUUCCUUAGCUUCCAGCCAUU NO 143 NO 167 SEQ ID UGGCCUGUCCUAAGACCUGCUCAGC SEQ ID CUUCUUCCUUAGCUUCCAGCCAUUG NO 144 NO 168 SEQ ID GGCCUGUCCUAAGACCUGCUCAGCU SEQ ID UUCUUCCUUAGCUUCCAGCCAUUGU NO 145 NO 169 SEQ ID GCCUGUCCUAAGACCUGCUCAGCUU SEQ ID UCUUCCUUAGCUUCCAGCCAUUGUG NO 146 NO 170 SEQ ID CCUGUCCUAAGACCUGCUCAGCUUC SEQ ID CUUCCUUAGCUUCCAGCCAUUGUGU NO 147 NO 171 SEQ ID CUGUCCUAAGACCUGCUCAGCUUCU SEQ ID UUCCUUAGCUUCCAGCCAUUGUGUU NO 148 NO 172 SEQ ID UGUCCUAAGACCUGCUCAGCUUCUU SEQ ID UCCUUAGCUUCCAGCCAUUGUGUUG NO 149 NO 173 SEQ ID GUCCUAAGACCUGCUCAGCUUCUUC SEQ ID CCUUAGCUUCCAGCCAUUGUGUUGA NO 150 NO 174 SEQ ID UCCUAAGACCUGCUCAGCUUCUUCC SEQ ID CUUAGCUUCCAGCCAUUGUGUUGAA NO 151 NO 175 SEQ ID CCUAAGACCUGCUCAGCUUCUUCCU SEQ ID UUAGCUUCCAGCCAUUGUGUUGAAU NO 152 NO 176 SEQ ID CUAAGACCUGCUCAGCUUCUUCCUU SEQ ID UAGCUUCCAGCCAUUGUGUUGAAUC NO 153 NO 177 SEQ ID UAAGACCUGCUCAGCUUCUUCCUUA SEQ ID AGCUUCCAGCCAUUGUGUUGAAUCC NO 154 NO 178 SEQ ID AAGACCUGCUCAGCUUCUUCCUUAG SEQ ID GCUUCCAGCCAUUGUGUUGAAUCCU NO 155 NO 179 SEQ ID AGACCUGCUCAGCUUCUUCCUUAGC SEQ ID CUUCCAGCCAUUGUGUUGAAUCCUU NO 156 NO 180 SEQ ID GACCUGCUCAGCUUCUUCCUUAGCU SEQ ID UUCCAGCCAUUGUGUUGAAUCCUUU NO 157 NO 181 SEQ ID ACCUGCUCAGCUUCUUCCUUAGCUU SEQ ID UCCAGCCAUUGUGUUGAAUCCUUUA NO 158 NO 182 SEQ ID CCUGCUCAGCUUCUUCCUUAGCUUC SEQ ID CCAGCCAUUGUGUUGAAUCCUUUAA NO 159 NO 183 SEQ ID CUGCUCAGCUUCUUCCUUAGCUUCC SEQ ID CAGCCAUUGUGUUGAAUCCUUUAAC NO 160 NO 184 SEQ ID UGCUCAGCUUCUUCCUUAGCUUCCA SEQ ID AGCCAUUGUGUUGAAUCCUUUAACA NO 161 NO 185 SEQ ID GCUCAGCUUCUUCCUUAGCUUCCAG SEQ ID GCCAUUGUGUUGAAUCCUUUAACAU NO 162 NO 186 SEQ ID CUCAGCUUCUUCCUUAGCUUCCAGC SEQ ID CCAUUGUGUUGAAUCCUUUAACAUU NO 163 NO 187 SEQ ID UCAGCUUCUUCCUUAGCUUCCAGCC SEQ ID CAUUGUGUUGAAUCCUUUAACAUUU NO 164 NO 188 DMD Gene Exon 44 SEQ ID UCAGCUUCUGUUAGCCACUG SEQ ID AGCUUCUGUUAGCCACUGAUUAAA NO 189 NO 214 SEQ ID UUCAGCUUCUGUUAGCCACU SEQ ID CAGCUUCUGUUAGCCACUGAUUAA NO 190 NO 215 A SEQ ID UUCAGCUUCUGUUAGCCACUG SEQ ID AGCUUCUGUUAGCCACUGAUUAAA NO 191 NO 216 SEQ ID UCAGCUUCUGUUAGCCACUGA SEQ ID AGCUUCUGUUAGCCACUGAU NO 192 NO 217 SEQ ID UUCAGCUUCUGUUAGCCACUGA SEQ ID GCUUCUGUUAGCCACUGAUU NO 193 NO 218 SEQ ID UCAGCUUCUGUUAGCCACUGA SEQ ID AGCUUCUGUUAGCCACUGAUU NO 194 NO 219 SEQ ID UUCAGCUUCUGUUAGCCACUGA SEQ ID GCUUCUGUUAGCCACUGAUUA NO 195 NO 220 SEQ ID UCAGCUUCUGUUAGCCACUGAU SEQ ID AGCUUCUGUUAGCCACUGAUUA NO 196 NO 221 SEQ ID UUCAGCUUCUGUUAGCCACUGAU SEQ ID GCUUCUGUUAGCCACUGAUUAA NO 197 NO 222 SEQ ID UCAGCUUCUGUUAGCCACUGAUU SEQ ID AGCUUCUGUUAGCCACUGAUUAA NO 198 NO 223 SEQ ID UUCAGCUUCUGUUAGCCACUGAUU SEQ ID GCUUCUGUUAGCCACUGAUUAAA NO 199 NO 224 SEQ ID UCAGCUUCUGUUAGCCACUGAUUA SEQ ID AGCUUCUGUUAGCCACUGAUUAAA NO 200 NO 225 SEQ ID UUCAGCUUCUGUUAGCCACUGAUA SEQ ID GCUUCUGUUAGCCACUGAUUAAA NO 201 NO 226 SEQ ID UCAGCUUCUGUUAGCCACUGAUUAA SEQ ID CCAUUUGUAUUUAGCAUGUUCCC NO 202 NO 227 SEQ ID UUCAGCUUCUGUUAGCCACUGAUUAA SEQ ID AGAUACCAUUUGUAUUUAGC NO 203 NO 228 SEQ ID UCAGCUUCUGUUAGCCACUGAUUAAA SEQ ID GCCAUUUCUCAACAGAUCU NO 204 NO 229 SEQ ID UUCAGCUUCUGUUAGCCACUGAUUAAA SEQ ID GCCAUUUCUCAACAGAUCUGUCA NO 205 NO 230 SEQ ID CAGCUUCUGUUAGCCACUG SEQ ID AUUCUCAGGAAUUUGUGUCUUUC NO 206 NO 231 SEQ ID CAGCUUCUGUUAGCCACUGAU SEQ ID UCUCAGGAAUUUGUGUCUUUC NO 207 NO 232 SEQ ID AGCUUCUGUUAGCCACUGAUU SEQ ID GUUCAGCUUCUGUUAGCC NO 208 NO 233 SEQ ID CAGCUUCUGUUAGCCACUGAUU SEQ ID CUGAUUAAAUAUCUUUAUAU C NO 209 NO 234 SEQ ID AGCUUCUGUUAGCCACUGAUUA SEQ ID GCCGCCAUUUCUCAACAG NO 210 NO 235 SEQ ID CAGCUUCUGUUAGCCACUGAUUA SEQ ID GUAUUUAGCAUGUUCCCA NO 211 NO 236 SEQ ID AGCUUCUGUUAGCCACUGAUUAA SEQ ID CAGGAAUUUGUGUCUUUC NO 212 NO 237 SEQ ID CAGCUUCUGUUAGCCACUGAUUAA SEQ ID UCAICUUCUGUUAGCCACUG NO 213 NO 575 SEQ ID UCAGCUUCUIUUAGCCACUG SEQ ID UCAGCUUCUGUUAGCCACUI NO 573 NO 576 SEQ ID UCAGCUUCUGUUAICCACUG NO 574 DMD Gene Exon 46 SEQ ID GCUUUUCUUUUAGUUGCUGCUCUUU SEQ ID CCAGGUUCAAGUGGGAUACUAGCAA NO 238 NO 265 SEQ ID CUUUUCUUUUAGUUGCUGCUCUUUU SEQ ID CAGGUUCAAGUGGGAUACUAGCAAU NO 239 NO 266 SEQ ID UUUUCUUUUAGUUGCUGCUCUUUUC SEQ ID AGGUUCAAGUGGGAUACUAGCAAUG NO 240 NO 267 SEQ ID UUUCUUUUAGUUGCUGCUCUUUUCC SEQ ID GGUUCAAGUGGGAUACUAGCAAUGU NO 241 NO 268 SEQ ID UUCUUUUAGUUGCUGCUCUUUUCCA SEQ ID GUUCAAGUGGGAUACUAGCAAUGUU NO 242 NO 269 SEQ ID UCUUUUAGUUGCUGCUCUUUUCCAG SEQ ID UUCAAGUGGGAUACUAGCAAUGUUA NO 243 NO 270 SEQ ID CUUUUAGUUGCUGCUCUUUUCCAGG SEQ ID UCAAGUGGGAUACUAGCAAUGUUAU NO 244 NO 271 SEQ ID UUUUAGUUGCUGCUCUUUUCCAGGU SEQ ID CAAGUGGGAUACUAGCAAUGUUAUC NO 245 NO 272 SEQ ID UUUAGUUGCUGCUCUUUUCCAGGUU SEQ ID AAGUGGGAUACUAGCAAUGUUAUCU NO 246 NO 273 SEQ ID UUAGUUGCUGCUCUUUUCCAGGUUC SEQ ID AGUGGGAUACUAGCAAUGUUAUCUG NO 247 NO 274 SEQ ID UAGUUGCUGCUCUUUUCCAGGUUCA SEQ ID GUGGGAUACUAGCAAUGUUAUCUGC NO 248 NO 275 SEQ ID AGUUGCUGCUCUUUUCCAGGUUCAA SEQ ID UGGGAUACUAGCAAUGUUAUCUGCU NO 249 NO 276 SEQ ID GUUGCUGCUCUUUUCCAGGUUCAAG SEQ ID GGGAUACUAGCAAUGUUAUCUGCUU NO 250 NO 277 SEQ ID UUGCUGCUCUUUUCCAGGUUCAAGU SEQ ID GGAUACUAGCAAUGUUAUCUGCUUC NO 251 NO 278 SEQ ID UCCUGCUCUUUUCCAGGUUCAAGUG SEQ ID GAUACUAGCAAUGUUAUCUGCUUCC NO 252 NO 279 SEQ ID GCUGCUCUUUUCCAGGUUCAAGUGG SEQ ID AUACUAGCAAUGUUAUCUGCUUCCU NO 253 NO 280 SEQ ID CUGCUCUUUUCCAGGUUCAAGUGGG SEQ ID UACUAGCAAUGUUAUCUGCUUCCUC NO 254 NO 281 SEQ ID UGCUCUUUUCCAGGUUCAAGUGGGA SEQ ID ACUAGCAAUGUUAUCUGCUUCCUCC NO 255 NO 282 SEQ ID GCUCUUUUCCAGGUUCAAGUGGGAC SEQ ID CUAGCAAUGUUAUCUGCUUCCUCCA NO 256 NO 283 SEQ ID CUCUUUUCCAGGUUCAAGUGGGAUA SEQ ID UAGCAAUGUUAUCUGCUUCCUCCAA NO 257 NO 284 SEQ ID UCUUUUCCAGGUUCAAGUGGGAUAC SEQ ID AGCAAUGUUAUCUGCUUCCUCCAAC NO 258 NO 285 SEQ ID UCUUUUCCAGGUUCAAGUGG SEQ ID GCAAUGUUAUCUGCUUCCUCCAACC NO 259 NO 286 SEQ ID CUUUUCCAGGUUCAAGUGGGAUACU SEQ ID CAAUGUUAUCUGCUUCCUCCAACCA NO 260 NO 287 SEQ ID UUUUCCAGGUUCAAGUGGGAUACUA SEQ ID AAUGUUAUCUGCUUCCUCCAACCAU NO 261 NO 288 SEQ ID UUUCCAGGUUCAAGUGGGAUACUAG SEQ ID AUGUUAUCUGCUUCCUCCAACCAUA NO 262 NO 289 SEQ ID UUCCAGGUUCAAGUGGGAUACUAGC SEQ ID UGUUAUCUGCUUCCUCCAACCAUAA NO 263 NO 290 SEQ ID UCCAGGUUCAAGUGGGAUACUAGCA NO 264 DMD Gene Exon 52 SEQ ID AGCCUCUUGAUUGCUGGUCUUGUUU SEQ ID UUGGGCAGCGGUAAUGAGUUCUUCC NO 291 NO 326 SEQ ID GCCUCUUGAUUGCUGGUCUUGUUUU SEQ ID UGGGCAGCGGUAAUGAGUUCUUCCA NO 292 NO 327 SEQ ID CCUCUUGAUUGCUGGUCUUGUUUUU SEQ ID GGGCAGCGGUAAUGAGUUCUUCCAA NO 293 NO 328 SEQ ID CCUCUUGAUUGCUGGUCUUG SEQ ID GGCAGCGGUAAUGAGUUCUUCCAAC NO 294 NO 329 SEQ ID CUCUUGAUUGCUGGUCUUGUUUUUC SEQ ID GCAGCGGUAAUGAGUUCUUCCAACU NO 295 NO 330 SEQ ID UCUUGAUUGCUGGUCUUGUUUUUCA SEQ ID CAGCGGUAAUGAGUUCUUCCAACUG NO 296 NO 331 SEQ ID CUUGAUUGCUGGUCUUGUUUUUCAA SEQ ID AGCGGUAAUGAGUUCUUCCAACUGG NO 297 NO 332 SEQ ID UUGAUUGCUGGUCUUGUUUUUCAAA SEQ ID GCGGUAAUGAGUUCUUCCAACUGGG NO 298 NO 333 SEQ ID UGAUUGCUGGUCUUGUUUUUCAAAU SEQ ID CGGUAAUGAGUUCUUCCAACUGGGG NO 299 NO 334 SEQ ID GAUUGCUGGUCUUGUUUUUCAAAUU SEQ ID GGUAAUGAGUUCUUCCAACUGGGGA NO 300 NO 335 SEQ ID GAUUGCUGGUCUUGUUUUUC SEQ ID GGUAAUGAGUUCUUCCAACUGG NO 301 NO 336 SEQ ID AUUGCUGGUCUUGUUUUUCAAAUUU SEQ ID GUAAUGAGUUCUUCCAACUGGGGAC NO 302 NO 337 SEQ ID UUGCUGGUCUUGUUUUUCAAAUUUU SEQ ID UAAUGAGUUCUUCCAACUGGGGACG NO 303 NO 338 SEQ ID UGCUGGUCUUGUUUUUCAAAUUUUG SEQ ID AAUGAGUUCUUCCAACUGGGGACGC NO 304 NO 339 SEQ ID GCUGGUCUUGUUUUUCAAAUUUUGG SEQ ID AUGAGUUCUUCCAACUGGGGACGCC NO 305 NO 340 SEQ ID CUGGUCUUGUUUUUCAAAUUUUGGG SEQ ID UGAGUUCUUCCAACUGGGGACGCCU NO 306 NO 341 SEQ ID UGGUCUUGUUUUUCAAAUUUUGGGC SEQ ID GAGUUCUUCCAACUGGGGACGCCUC NO 307 NO 342 SEQ ID GGUCUUGUUUUUCAAAUUUUGGGCA SEQ ID AGUUCUUCCAACUGGGGACGCCUCU NO 308 NO 343 SEQ ID GUCUUGUUUUUCAAAUUUUGGGCAG SEQ ID GUUCUUCCAACUGGGGACGCCUCUG NO 309 NO 344 SEQ ID UCUUGUUUUUCAAAUUUUGGGCAGC SEQ ID UUCUUCCAACUGGGGACGCCUCUGU NO 310 NO 345 SEQ ID CUUGUUUUUCAAAUUUUGGGCAGCG SEQ ID UCUUCCAACUGGGGACGCCUCUGUU NO 311 NO 346 SEQ ID UUGUUUUUCAAAUUUUGGGCAGCGG SEQ ID CUUCCAACUGGGGACGCCUCUGUUC NO 312 NO 347 SEQ ID UGUUUUUCAAAUUUUGGGCAGCGGU SEQ ID UUCCAACUGGGGACGCCUCUGUUCC NO 313 NO 348 SEQ ID GUUUUUCAAAUUUUGGGCAGCGGUA SEQ ID UCCAACUGGGGACGCCUCUGUUCCA NO 314 NO 349 SEQ ID UUUUUCAAAUUUUGGGCAGCGGUAA SEQ ID CCAACUGGGGACGCCUCUGUUCCAA NO 315 NO 350 SEQ ID UUUUCAAAUUUUGGGCAGCGGUAAU SEQ ID CAACUGGGGACGCCUCUGUUCCAAA NO 316 NO 351 SEQ ID UUUCAAAUUUUGGGCAGCGGUAAUG SEQ ID AACUGGGGACGCCUCUGUUCCAAAU NO 317 NO 352 SEQ ID UUCAAAUUUUGGGCAGCGGUAAUGA SEQ ID ACUGGGGACGCCUCUGUUCCAAAUC NO 318 NO 353 SEQ ID UCAAAUUUUGGGCAGCGGUAAUGAG SEQ ID CUGGGGACGCCUCUGUUCCAAAUCC NO 319 NO 354 SEQ ID CAAAUUUUGGGCAGCGGUAAUGAGU SEQ ID UGGGGACGCCUCUGUUCCAAAUCCU NO 320 NO 355 SEQ ID AAAUUUUGGGCAGCGGUAAUGAGUU SEQ ID GGGGACGCCUCUGUUCCAAAUCCUG NO 321 NO 356 SEQ ID AAUUUUGGGCAGCGGUAAUGAGUUC SEQ ID GGGACGCCUCUGUUCCAAAUCCUGC NO 322 NO 357 SEQ ID AUUUUGGGCAGCGGUAAUGAGUUCU SEQ ID GGACGCCUCUGUUCCAAAUCCUGCA NO 323 NO 358 SEQ ID UUUUGGGCAGCGGUAAUGAGUUCUU SEQ ID GACGCCUCUGUUCCAAAUCCUGCAU NO 324 NO 359 SEQ ID UUUGGGCAGCGGUAAUGAGUUCUUC NO 325 DMD Gene Exon 50 SEQ ID CCAAUAGUGGUCAGUCCAGGAGCUA SEQ ID CUAGGUCAGGCUGCUUUGCCCUCAG NO 360 NO 386 SEQ ID CAAUAGUGGUCAGUCCAGGAGCUAG SEQ ID UAGGUCAGGCUGCUUUGCCCUCAGC NO 361 NO 387 SEQ ID AAUAGUGGUCAGUCCAGGAGCUAGG SEQ ID AGGUCAGGCUGCUUUGCCCUCAGCU NO 362 NO 388 SEQ ID AUAGUGGUCAGUCCAGGAGCUAGGU SEQ ID GGUCAGGCUGCUUUGCCCUCAGCUC NO 363 NO 389 SEQ ID AUAGUGGUCAGUCCAGGAGCU SEQ ID GUCAGGCUGCUUUGCCCUCAGCUCU NO 364 NO 390 SEQ ID UAGUGGUCAGUCCAGGAGCUAGGUC SEQ ID UCAGGCUGCUUUGCCCUCAGCUCUU NO 365 NO 391 SEQ ID AGUGGUCAGUCCAGGAGCUAGGUCA SEQ ID CAGGCUGCUUUGCCCUCAGCUCUUG NO 366 NO 392 SEQ ID GUGGUCAGUCCAGGAGCUAGGUCAG SEQ ID AGGCUGCUUUGCCCUCAGCUCUUGA NO 367 NO 393 SEQ ID UGGUCAGUCCAGGAGCUAGGUCAGG SEQ ID GGCUGCUUUGCCCUCAGCUCUUGAA NO 368 NO 394 SEQ ID GGUCAGUCCAGGAGCUAGGUCAGGC SEQ ID GCUGCUUUGCCCUCAGCUCUUGAAG NO 369 NO 395 SEQ ID GUCAGUCCAGGAGCUAGGUCAGGCU SEQ ID CUGCUUUGCCCUCAGCUCUUGAAGU NO 370 NO 396 SEQ ID UCAGUCCAGGAGCUAGGUCAGGCUG SEQ ID UGCUUUGCCCUCAGCUCUUGAAGUA NO 371 NO 397 SEQ ID CAGUCCAGGAGCUAGGUCAGGCUGC SEQ ID GCUUUGCCCUCAGCUCUUGAAGUAA NO 372 NO 398 SEQ ID AGUCCAGGAGCUAGGUCAGGCUGCU SEQ ID CUUUGCCCUCAGCUCUUGAAGUAAA NO 373 NO 399 SEQ ID GUCCAGGAGCUAGGUCAGGCUGCUU SEQ ID UUUGCCCUCAGCUCUUGAAGUAAAC NO 374 NO 400 SEQ ID UCCAGGAGCUAGGUCAGGCUGCUUU SEQ ID UUGCCCUCAGCUCUUGAAGUAAACG NO 375 NO 401 SEQ ID CCAGGAGCUAGGUCAGGCUGCUUUG SEQ ID UGCCCUCAGCUCUUGAAGUAAACGG NO 376 NO 402 SEQ ID CAGGAGCUAGGUCAGGCUGCUUUGC SEQ ID GCCCUCAGCUCUUGAAGUAAACGGU NO 377 NO 403 SEQ ID AGGAGCUAGGUCAGGCUGCUUUGCC SEQ ID CCCUCAGCUCUUGAAGUAAACGGUU NO 378 NO 404 SEQ ID GGAGCUAGGUCAGGCUGCUUUGCCC SEQ ID CCUCAGCUCUUGAAGUAAAC NO 379 NO 405 SEQ ID GAGCUAGGUCAGGCUGCUUUGCCCU SEQ ID CCUCAGCUCUUGAAGUAAACG NO 380 NO 406 SEQ ID AGCUAGGUCAGGCUGCUUUGCCCUC SEQ ID CUCAGCUCUUGAAGUAAACG NO 381 NO 407 SEQ ID GCUAGGUCAGGCUGCUUUGCCCUCA SEQ ID CCUCAGCUCUUGAAGUAAACGGUUU NO 382 NO 408 SEQ ID CUCAGCUCUUGAAGUAAACGGUUUA SEQ ID UCAGCUCUUGAAGUAAACGGUUUAC NO 383 NO 409 SEQ ID CAGCUCUUGAAGUAAACGGUUUACC SEQ ID AGCUCUUGAAGUAAACGGUUUACCG NO 384 NO 410 SEQ ID GCUCUUGAAGUAAACGGUUUACCGC SEQ ID CUCUUGAAGUAAACGGUUUACCGCC NO 385 NO 411 DMD Gene Exon 43 SEQ ID CCACAGGCGUUGCACUUUGCAAUGC SEQ ID  UCUUCUUGCUAUGAAUAAUGUCAAU NO 412 NO 443 SEQ ID CACAGGCGUUGCACUUUGCAAUGCU SEQ ID CUUCUUGCUAUGAAUAAUGUCAAUC NO 413 NO 444 SEQ ID ACAGGCGUUGCACUUUGCAAUGCUG SEQ ID UUCUUGCUAUGAAUAAUGUCAAUCC NO 414 NO 445 SEQ ID CAGGCGUUGCACUUUGCAAUGCUGC SEQ ID UCUUGCUAUGAAUAAUGUCAAUCCG NO 415 NO 446 SEQ ID AGGCGUUGCACUUUGCAAUGCUGCU SEQ ID CUUGCUAUGAAUAAUGUCAAUCCGA NO 416 NO 447 SEQ ID GGCGUUGCACUUUGCAAUGCUGCUG SEQ ID UUGCUAUGAAUAAUGUCAAUCCGAC NO 417 NO 448 SEQ ID GCGUUGCACUUUGCAAUGCUGCUGU SEQ ID UGCUAUGAAUAAUGUCAAUCCGACC NO 418 NO 449 SEQ ID CGUUGCACUUUGCAAUGCUGCUGUC SEQ ID GCUAUGAAUAAUGUCAAUCCGACCU NO 419 NO 450 SEQ ID CGUUGCACUUUGCAAUGCUGCUG SEQ ID CUAUGAAUAAUGUCAAUCCGACCUG NO 420 NO 451 SEQ ID GUUGCACUUUGCAAUGCUGCUGUCU SEQ ID UAUGAAUAAUGUCAAUCCGACCUGA NO 421 NO 452 SEQ ID UUGCACUUUGCAAUGCUGCUGUCUU SEQ ID AUGAAUAAUGUCAAUCCGACCUGAG NO 422 NO 453 SEQ ID UGCACUUUGCAAUGCUGCUGUCUUC SEQ ID UGAAUAAUGUCAAUCCGACCUGAGC NO 423 NO 454 SEQ ID GCACUUUGCAAUGCUGCUGUCUUCU SEQ ID GAAUAAUGUCAAUCCGACCUGAGCU NO 424 NO 455 SEQ ID CACUUUGCAAUGCUGCUGUCUUCUU SEQ ID AAUAAUGUCAAUCCGACCUGAGCUU NO 425 NO 456 SEQ ID ACUUUGCAAUGCUGCUGUCUUCUUG SEQ ID AUAAUGUCAAUCCGACCUGAGCUUU NO 426 NO 457 SEQ ID CUUUGCAAUGCUGCUGUCUUCUUGC SEQ ID UAAUGUCAAUCCGACCUGAGCUUUG NO 427 NO 458 SEQ ID UUUGCAAUGCUGCUGUCUUCUUGCU SEQ ID AAUGUCAAUCCGACCUGAGCUUUGU NO 428 NO 459 SEQ ID UUGCAAUGCUGCUGUCUUCUUGCUA SEQ ID AUGUCAAUCCGACCUGAGCUUUGUU NO 429 NO 460 SEQ ID UGCAAUGCUGCUGUCUUCUUGCUAU SEQ ID UGUCAAUCCGACCUGAGCUUUGUUG NO 430 NO 461 SEQ ID GCAAUGCUGCUGUCUUCUUGCUAUG SEQ ID GUCAAUCCGACCUGAGCUUUGUUGU NO 431 NO 462 SEQ ID CAAUGCUGCUGUCUUCUUGCUAUGA SEQ ID UCAAUCCGACCUGAGCUUUGUUGUA NO 432 NO 463 SEQ ID AAUGCUGCUGUCUUCUUGCUAUGAA SEQ ID CAAUCCGACCUGAGCUUUGUUGUAG NO 433 NO 464 SEQ ID AUGCUGCUGUCUUCUUGCUAUGAAU SEQ ID AAUCCGACCUGAGCUUUGUUGUAGA NO 434 NO 465 SEQ ID UGCUGCUGUCUUCUUGCUAUGAAUA SEQ ID AUCCGACCUGAGCUUUGUUGUAGAC NO 435 NO 466 SEQ ID GCUGCUGUCUUCUUGCUAUGAAUAA SEQ ID UCCGACCUGAGCUUUGUUGUAGACU NO 436 NO 467 SEQ ID CUGCUGUCUUCUUGCUAUGAAUAAU SEQ ID CCGACCUGAGCUUUGUUGUAGACUA NO 437 NO 468 SEQ ID UGCUGUCUUCUUGCUAUGAAUAAUG SEQ ID CGACCUGAGCUUUGUUGUAG NO 438 NO 469 SEQ ID GCUGUCUUCUUGCUAUGAAUAAUGU SEQ ID CGACCUGAGCUUUGUUGUAGACUAU NO 439 NO 470 SEQ ID CUGUCUUCUUGCUAUGAAUAAUGUC SEQ ID GACCUGAGCUUUGUUGUAGACUAUC NO 440 NO 471 SEQ ID UGUCUUCUUGCUAUGAAUAAUGUCA SEQ ID ACCUGAGCUUUGUUGUAGACUAUCA NO 441 NO 472 SEQ ID GUCUUCUUGCUAUGAAUAAUGUCAA SEQ ID CCUGAGCUUUGUUGUAGACUAUC NO 442 NO 473 DMD Gene Exon 6 SEQ ID CAUUUUUGACCUACAUGUGG SEQ ID AUUUUUGACCUACAUGGGAAA G NO 474 NO 479 SEQ ID UUUGACCUACAUGUGGAAAG SEQ ID UACGAGUUGAUUGUCGGACCCAG NO 475 NO 480 SEQ ID UACAUUUUUGACCUACAUGUGGAAA SEQ ID GUGGUCUCCUUACCUAUGACUGUGG NO 476 G NO 481 SEQ ID GGUCUCCUUACCUAUGA SEQ ID UGUCUCAGUAAUCUUCUUACCUAU NO 477 NO 482 SEQ ID UCUUACCUAUGACUAUGGAUGAGA NO 478 DMD Gene Exon 7 SEQ ID UGCAUGUUCCAGUCGUUGUGUGG SEQ ID AUUUACCAACCUUCAGGAUCGAGUA NO 483 NO 485 SEQ ID CACUAUUCCAGUCAAAUAGGUCUGG SEQ ID GGCCUAAAACACAUACACAUA NO 484 NO 486 DMD Gene Exon 8 SEQ ID GAUAGGUGGUAUCAACAUCUGUAA SEQ ID UGUUGUUGUUUAUGCUCAUU NO 487 NO 490 SEQ ID GAUAGGUGGUAUCAACAUCUG SEQ ID GUACAUUAAGAUGGACUUC NO 488 NO 491 SEQ ID CUUCCUGGAUGGCUUGAAU NO 489 DMD Gene Exon 55 SEQ ID CUGUUGCAGUAAUCUAUGAG SEQ ID UGCCAUUGUUUCAUCAGCUCUUU NO 492 NO 495 SEQ ID UGCAGUAAUCUAUGAGUUUC SEQ ID UCCUGUAGGACAUUGGCAGU NO 493 NO 496 SEQ ID GAGUCUUCUAGGAGCCUU SEQ ID CUUGGAGUCUUCUAGGAGCC NO 494 NO 497 DMD Gene Exon 2 SEQ ID CCAUUUUGUGAAUGUUUUCUUUUG SEQ ID GAAAAUUGUGCAUUUACCCAUUUU NO 498 AACAUC NO 500 SEQ ID CCCAUUUUGUGAAUGUUUUCUUUU SEQ ID UUGUGCAUUUACCCAUUUUGUG NO 499 NO 501 DMD Gene Exon 11 SEQ ID CCCUGAGGCAUUCCCAUCUUGAAU SEQ ID  CUUGAAUUUAGGAGAUUCAUCUG NO 502 NO 504 SEQ ID AGGACUUACUUGCUUUGUUU SEQ ID CAUCUUCUGAUAAUUUUCCUGUU NO 503 NO 505 DMD Gene Exon 17 SEQ ID CCAUUACAGUUGUCUGUGUU SEQ ID UAAUCUGCCUCUUCUUUUGG NO 506 NO 508 SEQ ID UGACAGCCUGUGAAAUCUGUGAG NO 507 DMD Gene Exon 19 SEQ ID CAGCAGUAGUUGUCAUCUGC SEQ ID GCCUGAGCUGAUCUGCUGGCAUCUUG NO 509 NO 511 CAGUU SEQ ID GCCUGAGCUGAUCUGCUGGCAUCUU SEQ ID UCUGCUGGCAUCUUGC NO 510 GC NO 512 DMD Gene Exon 21 SEQ ID GCCGGUUGACUUCAUCCUGUGC SEQ ID CUGCAUCCAGGAACAUGGGUCC NO 513 NO 516 SEQ ID GUCUGCAUCCAGGAACAUGGGUC SEQ ID GUUGAAGAUCUGAUAGCCGGUUGA NO 514 NO 517 SEQ ID UACUUACUGUCUGUAGCUCUUUCU NO 515 DMD Gene Exon 57 SEQ ID UAGGUGCCUGCCGGCUU SEQ ID CUGAACUGCUGGAAAGUCGCC NO 518 NO 520 SEQ ID UUCAGCUGUAGCCACACC SEQ ID CUGGCUUCCAAAUGGGACCUGAAAAA NO 519 NO 521 GAAC DMD Gene Exon 59 SEQ ID CAAUUUUUCCCACUCAGUAUU NO 522 SEQ ID UCCUCAGGAGGCAGCUCUAAAU SEQ ID UUGAAGUUCCUGGAGUCUU NO 524 NO 523 DMD Gene Exon 62 SEQ ID UGGCUCUCUCCCAGGG SEQ ID GGGCACUUUGUUUGGCG NO 525 NO 527 SEQ ID GAGAUGGCUCUCUCCCAGGGACCCU NO 526 GG DMD Gene Exon 63 SEQ ID GGUCCCAGCAAGUUGUUUG SEQ ID GUAGAGCUCUGUCAUUUUGGG NO 528 NO 530 SEQ ID UGGGAUGGUCCCAGCAAGUUGUUUG NO 529 DMD Gene Exon 65 SEQ ID GCUCAAGAGAUCCACUGCAAAAAAC SEQ ID UCUGCAGGAUAUCCAUGGGCUGGUC NO 531 NO 533 SEQ ID GCCAUACGUACGUAUCAUAAACAUU NO 532 C DMD Gene Exon 66 SEQ ID GAUCCUCCCUGUUCGUCCCCUAUUA NO 534 UG DMD Gene Exon 69 SEQ ID UGCUUUAGACUCCUGUACCUGAUA NO 535 DMD Gene Exon 75 SEQ ID GGCGGCCUUUGUGUUGAC SEQ ID CCUUUAUGUUCGUGCUGCU NO 536 NO 538 SEQ ID GGACAGGCCUUUAUGUUCGUGCUGC NO 537 Human IGF-1 Isoform 4 amino acid sequence SEQ ID NO 577: MGKISSLPTQLFKCCFCDFLKVKMHTMSSSHLFYLALCLLTFTSSATAGPETLCGAELV DALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA RSVRAQRHTDMPKTQKEVHLKNASRGSAGNKNYRM