AAV delivery system for full-length dystrophin

Abstract

Disclosed herein are methods and systems for expressing nucleic acid molecules encoding a functional, non-fragmented dystrophin protein and assembling the non-truncated protein in a host cell. Also disclosed are vectors including the nucleic acid molecules, such as in a split-gene orientation for trans-splicing of a full-length or near full-length dystrophin protein in a host cell, and pharmaceutical compositions including the same. Further disclosed are methods of treating a disorder characterized by a dystrophin protein deficiency, such as muscular dystrophy, involving administering a therapeutically effective amount of the nucleic acid molecules to a subject in need thereof.

Description

AAV DELIVERY SYSTEM FOR FULL-LENGTH DYSTROPHINSTATEMENT OF GOVERNMENTAL RIGHTS

[0001] This invention was made with government support under HL 170260 awarded byNational Institutes of Health. The Government has certain rights in the invention.INCORPORATION OF SEQUENCE LISTING

[0002] A paper copy of the Sequence Listing and a computer readable form of the sequence containing the file named “2024-062-02-WO st26 sequence listing.xml”, which is 215.075 bytes in size, are provided herein and are herein incorporated by reference. This Sequence Listing consists ofSEQ ID NOs;1-68.FIELD OF THE INVENTION

[0003] This disclosure generally relates to nucleic acid molecules encoding a functional dystrophin protein, such as a full-length, non-fragmented dystrophin protein, and methods and systems for expressing and assembling the same in a host cell. The disclosure further relates to vectors including the nucleic acid molecules, such as in a split-gene orientation for trans-splicing of a non-fragmented dystrophin protein. Additionally, the disclosure relates to methods of treating a condition characterized by dystrophin deficiency, for example, a type of muscular dystrophy.BACKGROUND

[0004] Dystrophin, the largest known human gene with a molecular weight of 427 kDa, is a molecular linker between the intracellular actin and extracellular matrix that is crucial to muscle contractility and integrity. Disrupted expression of dystrophin leads to repeated cycles of muscle damage and repair, which eventually exhaust the regenerative capacity of muscle stem cells andcause fibrosis and fatty replacement. The progressive loss of muscle mass and function affects the skeletal, cardiac, and respiratory muscles, leading to reduced mobility, cardiomyopathy, respiratory failure, and early death. One example of a condition characterized by disrupted expression of dystrophin and consequent deficiency thereof is Duchenne Muscular Dystrophy(DMD), an X-linked inherited condition. Initially, the effects of DMD manifest within the proximal skeletal muscles of the limbs, reducing the dystrophin deficient subject's mobility, and eventually progress to respiratory and cardiac systems. Invasive support systems are necessary to promote survival. However, death typically occurs between the second and third decade of a patient’s life.

[0005] Current strategies to correct dystrophin deficiency or disrupted expression of dystrophin include delivering a truncated, semi-functional dystrophin protein, multiplex CRISPR- mediated deletion of a dystrophin mutation hotspot, and NHEJ-mediated genome editing approaches to restore the reading frame required for dystrophin production. However, all of these strategies suffer drawbacks and may only benefit certain patient cohorts. In one example, miniaturized dystrophin (micro-dystrophin or μDys) fails to provide full protection for striated muscles as it lacks many important functional domains that are within full-length dystrophin.Accordingly, there is a need to provide a therapeutic strategy that can treat dystrophin deficiency regardless of the etiology. Additionally, there exists a need to express a fully functional dystrophin protein in a host cell, such as a whole, non-truncated dystrophin protein. Aspects of the invention disclosed herein address these needs.INCORPORATION BY REFERENCE

[0006] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually, andas if each is fully set forth herein. However, where such reference is made, and whether to patents, publications, non-patent literature, or other sources of information, it is for the general purpose of providing context for discussing features of the invention. Accordingly, unless specifically stated otherwise, the reference is not to be construed as an admission that the document or underlying information, in any jurisdiction, is prior art, or forms part of the common general knowledge in the art.SUMMARY OF THE INVENTION

[0007] A first aspect of the invention includes systems, such as expression systems, for expressing a full-length or near-full-length dystrophin protein in a cell.

[0008] A second aspect of the invention includes triple myotropic adeno-associated virus vector systems for expressing a full-length dystrophin protein or dual myotropic adeno-associated virus vector systems for expressing a near-full-length dystrophin protein in a cell.

[0009] A third aspect of the invention includes pharmaceutical compositions containing disclosed expression systems.

[0010] A fourth aspect of the invention includes methods of treating a subject having a dystrophin deficiency.

[0011] A fifth aspect of the invention includes methods for transducing a cell with multiple vectors to produce a full-length or near-full-length dystrophin protein.

[0012] A first embodiment is a system for expressing a full-length or near-full-length dystrophin protein in a cell including multiple independent virus vectors encoding fragments of the dystrophin protein, where the fragments are trans-spliced by at least one split intein.

[0013] A second embodiment is a system where the multiple independent virus vectors comprise: I) a first independent vector including a nucleotide sequence that has at least 90%sequence identity to SEQ ID NO: 3, or the complement thereof; II) a second independent vector including a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO:5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; and III) a third independent vector including a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO:7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof.

[0014] A third embodiment is system where at least one of the virus vectors includes a CMV promoter or a muscle-specific promoter.

[0015] A fourth embodiment is a system where the muscle-specific promoter includes a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:27 or the complement thereof; or a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:28 or the complement thereof.

[0016] A fifth embodiment is a system where the at least one split intein is Cfa, GP41-1,IMPDH-1, or a combination thereof.

[0017] A sixth embodiment is a system where the at least one split intein is Cfa, which has100% sequence identity to the full length of the amino acid sequence of SEQ ID NO:31 and / orSEQ ID NO:32.

[0018] A seventh embodiment is a system where the at least one split intein is GP41-1, which has 100% sequence identity to the full length of the amino acid sequence of SEQ ID NO:33 and / orSEQ ID NO:34.

[0019] An eighth embodiment is a system where the at least one split intein is IMPDH-1, which has 100% sequence identity to the full length of the amino acid sequence of SEQ ID NO:35 and / or SEQ ID NO: 36.

[0020] A ninth embodiment is a system where the virus vector is an adeno-associated virus vector.

[0021] A tenth embodiment is a system where the adeno-associated virus vector is a myotropic adeno-associated virus vector.

[0022] An eleventh embodiment is a triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein in a cell including: I) a first independent vector including a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO: 3; II) a second independent vector including a nucleotide sequence encoding an M fragment that has at least 90% to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; and III) a third independent vector including a nucleotide sequence encoding a C fragment that has at least 90% to any one of SEQ ID NO: 7, SEQ ID NO: 11, SEQID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof.

[0023] A twelfth embodiment is a triple myotropic adeno-associated virus vector system whereI) the first independent vector includes the nucleotide sequence of SEQ ID NO: 3 or the complement thereof; II) the second independent vector includes the nucleotide sequence of SEQID NO: 19 or the complement thereof; and III) the second independent vector includes the nucleotide sequence SEQ ID NO: 21 or the complement thereof.

[0024] A thirteenth embodiment is a triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein in a mammalian cell.

[0025] A fourteenth embodiment is a triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein a human cell.

[0026] A fifteenth embodiment is a triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein where the full-length dystrophin protein includes an amino acid sequence that has at least 90% sequence identity to the full length of SEQ ID NO: 2.

[0027] A sixteenth embodiment is a triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein where the full-length dystrophin protein includes or consists of the full length of SEQ ID NO: 2.

[0028] A seventeenth embodiment is a pharmaceutical composition including the system of any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0029] An eighteenth embodiment is method of treating a subject having a dystrophin deficiency by administering the system or the pharmaceutical composition of any one of the preceding embodiments to the subject.

[0030] A nineteenth embodiment is method of treating a subject that has a muscular dystrophy.

[0031] A twentieth embodiment is method of treating a subject that has Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, a limb-girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.

[0032] A twenty-first embodiment is method of treating a subject where the subject is a mammal.

[0033] A twenty-second embodiment is method of treating a mammal where the mammal is a human.

[0034] A twenty-third embodiment is a method for transducing a cell with the system of any one of the preceding embodiments.

[0035] A twenty -fourth embodiment is a method for transducing a cell with multiple vectors to produce a full-length dystrophin protein, where the cell is transduced with: I) a first independent myotropic adeno-associated virus vector including a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO: 3; II) a second independent myotropic adeno-associated virus vector including a nucleotide sequence encoding an M fragment that has at least 90% to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; and III) a third independent myotropic adeno-associated virus vector including the nucleotide sequence encoding a C fragment that has at least 90% to any one of SEQ ID NO: 7,SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof; where the vg / kg ratio of the first to the second to the third independent myotropic adeno-associated virus vector is 1 : 1 :1, 1 :2: 1, 1 :2:2, 2:1 : 1, 2:2: 1, or 2: 1 :2.

[0036] A twenty-fifth embodiment is a method for transducing a cell with multiple vectors to produce a full-length dystrophin protein, where the cell is a mammalian cell.

[0037] A twenty-sixth embodiment is a method for transducing a mammalian cell with multiple vectors to produce a full-length dystrophin protein, where the mammalian cell is a human muscle cell.

[0038] A twenty-seventh embodiment is a system where the multiple independent virus vectors comprise: I) a first independent vector comprising a nucleotide sequence that has at least90% sequence identity to SEQ ID NO:39 or the complement thereof; II) a second independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:53 or the complement thereof; and III) a third independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:59 or the complement thereof.

[0039]

[0040] A twenty-eighth embodiment is a method for transducing a cell with multiple vectors to produce a full-length dystrophin protein, wherein the cell is transduced with: I) a first independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO:39, or the complement thereof; and II) a second independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an M fragment that has at least 90% to SEQ ID NO:53, or the complement thereof; and III) a third independent myotropic adeno-associated virus vector comprising the nucleotide sequence encoding a C fragment that has at least 90% to SEQ IDNO:59, or the complement thereof; wherein the vg / kg ratio of the first to the second to the third independent myotropic adeno-associated virus vector is 1 : 1 : 1 to 1 : 1 : 1.4.

[0041] A twenty-ninth embodiment is a system for expressing a not full-length dystrophin protein in a cell comprising two independent virus vectors encoding fragments of the full-length dystrophin protein, wherein the fragments are trans-spliced by at least one split intein.

[0042] A thirtieth embodiment is a system for expressing a not full-length dystrophin protein in a cell comprising two independent virus vectors encoding fragments of the full-length dystrophin protein, wherein the two independent virus vectors comprise: I) a first independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQID NO: 43, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:63, SEQ ID NO:65 or SEQ IDNO:67, or the complement thereof; and II) a second independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO: 17, SEQ ID NO: 21,SEQ ID NO: 61, or the complement thereof; andBRIEF DESCRIPTION OF THE FIGURES

[0043] The accompanying drawings are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments, and together with the description serve to explain the principles of the disclosure.

[0044] FIG. 1A is a diagram showing the domain structure of full-length (FL) dystrophin, the two split sites, the relative initiation sites of Dp260 and Dp 140 isoforms, and the three split fragments fused with inteins (Dys-N1, M1, and C1); the antigen epitopes for three different dystrophin antibodies (anti-N, anti-M and anti-C) are also labeled.

[0045] FIG. IB shows Western blot analysis of dystrophin expression in HEK293 cells transfected with or without the Dys-N 1 , Ml , and C 1 constructs at different molar ratios; WT mouse skeletal muscle lysate was loaded as a positive control, and GAPDH was used as a loading control.Data represented as mean ± SEM.

[0046] FIG. 2A is a diagram showing the predicted structure of the Hinge 3 domain with theMl / Cl and M2 / C2 split sites marked by the arrows and the three residues at each side of split sites labeled.

[0047] FIGs. 2B, 2H, and 2N show Western blot analysis of dystrophin expression inHEK293 cells transfected with or without different versions of Dys-N, M and C constructs at a molar ratio of 4:2; 1; HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control (FL Ctrl), and GAPDH was used as a loading control.

[0048] FIGs. 2C, 2D, 2E, 2F, 21, 2J, 2K, 2L, 20, 2P, 2Q, and 2R show densitometry quantification of the FL dystrophin band intensity (FIGs 2C, 21, and 20), the ratio of unassembledN versus FL (FIGs. 2D, 2J, and 2P), the ratio of unassembled M versus FL (FIGs. 2E, 2K, and2Q) and the ratio of unassembled C versus FL (FIGs 2F, 2L, and 2R); data was analyzed usingone-way ANOVA with Turkey’s multiple comparisons test for three groups and two-tailed unpaired Student’s t test for two groups; data presented as mean ± SEM.

[0049] FIGs 2G and 2M are diagrams showing the M and C constructs at the split sites with the -1 to -3 and +1 to +3 residues in the dystrophin exteins labeled; the mutated amino acids are labeled in purple (g) and yellow (m).

[0050] FIGs. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, and 31 show the ratio of partially assembled products versus FL dystrophin as determined by densitometry quantification of the Western blotting data shown in FIGs. 2B, 2H, and 2N; data analyzed using one-way ANOVA withTurkey’s multiple comparisons test for three groups and two-tailed unpaired Student’s t test for two groups.

[0051] FIG. 4A is a diagram showing the C7 and C8 constructs with the position of two different poly-adenylation signals before the transgene.

[0052] FIG. 4B shows Western blotting analysis of dystrophin expression in HEK293 cells transfected with or without different versions of Dys-N, M and C constructs at a molar ratio of4:2: 1; HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control (Ctrl), and GAPDH was used as a loading control.

[0053] FIGs. 4C, 4D, 4E, 4F, 4G, 4H, and 41 show densitometry quantification of the FL dystrophin band intensity (FIG. 4C), the ratio of unassembled N, M or C versus FL (FIGs. .4D-4F), and the ratio of partially assembled products versus FL (FIGs. 4G-4I).

[0054] FIG. 5A is a diagram depicting retro-orbital injection of MyoAAV4A carrying Dys-N1 / M3 / C6, the three MyoAAV4A constructs, and their respective doses administered.

[0055] FIG. 5B shows immunofluorescence images of GA muscle sections from WT and mdx^ mice treated with or without AAV (10 weeks of age, n=5 per group), stained with threedifferent anti -dystrophin antibodies recognizing N, M and C fragment, respectively; scale bar= 50 μm.

[0056] FIG. 5C shows quantification of dystrophin-positive muscle fibers in GA muscles of10-week-old mdx4cvmice treated with or without AAV (n=5 per group, two-tailed unpairedStudent’s t test); data are mean ± SEM.

[0057] FIG. 5D shows Western blot analysis of dystrophin expression in GA muscles fromWT and mdx4cvmice treated with or without AAV (10 weeks of age, n=3 per group).

[0058] FIG. 5E shows immunofluorescence staining of GA muscle sections from WT and mdx4cvmice treated with or without AAV (10 weeks of age, n=5 per group) using the antibodies against the dystrophin-glycoprotein complex (DGC) components including α-SG, β-SG, α-DG, β-DG, nNOS and α-DB; scale bar= 50 μm.

[0059] FIGs. 6A and 6B show immunofluorescence staining of heart (FIG. 6A) and diaphragm (FIG. 6B) muscle sections of WT and mdx4cvmice (n = 5 per group; 10 weeks of age) with anti-dystrophin antibodies; scale bar= 50 μm.

[0060] FIGs. 6C and 6D show quantification of dystrophin-positive cardiomyocytes in heart(FIG. 6C) or muscle fibers in diaphragm muscles (FIG. 6D) of 10-week-old mdx4cvmice treated with or without AAV (n=5 per group).

[0061] FIGs. 6E and 6F show Western blot analysis of dystrophin expression in heart and diaphragm muscles from WT and mdx4cvmice treated with or without AAV (10 weeks of age, n=3 per group); 6 μg total proteins from WT diaphragm muscles were loaded per lane whereas 30 μg were loaded for the other lanes; data analyzed by two-tailed unpaired Student’s t test.

[0062] FIG. 7 shows the results of in vivo studies. All animal experiments were performed inWT and mdx4cvmale mice with the C57BL / 6J genetic background. Data are mean ± SEM.Statistical analyses were performed by one-way ANOVA with Turkey’s multiple comparisons test except otherwise specified.

[0063] FIG. 7 A shows measurement of serum creatinine kinase (CK) in 8-week-old WT and mdx4cvmice with or without AAV treatment.

[0064] FIG. 7B shows tetanic torque measurements of the posterior compartment muscles of the mice (n = 8 WT, 10 mdx4cvand 11 AAV -treated mdx4cv; 8-12 weeks of age).

[0065] FIG. 7C shows measurement of hanging time prior to mice falling from wire mesh(n = 5 WT, 5 mdx4cv, and 5 AAV-treated mdx4cv; 17 weeks of age).

[0066] FIG. 7D shows H&E staining, immunofluorescence staining with anti-laminin0.2 / DAPI and Masson’s Trichrome staining images of gastrocnemius muscle sections (n = 5 per group; 10 weeks of age); scale bar= 50 μm.

[0067] FIG. 7E shows measurement of centrally nucleated fibers (CNF) in the gastrocnemius muscles of 10-week-old mdx4cvmice with or without AAV treatment (n=5 each, two-tailed unpaired t test).

[0068] FIG. 7F and 7G show muscle fiber size measurement and distribution in gastrocnemius muscles of the mice at 10 weeks of age (n = 5 WT, 5 mdx4cvand 6 AAV-treated mdx4c'y

[0069] FIG. 7H shows quantitative analysis of fibrotic area in the gastrocnemius muscle sections of the mice at 10 weeks of age (n = 3 per group).

[0070] FIGs. 71 and 7 J shows measurement of serum AST (FIG. 71) and ALT (FIG. 7 J) from the mice at 9 weeks of age (n = 8 WT, 9 mdx4"'' and 10 AAV-treated mdx4cv\

[0071] FIG. 8 shows histopathological examination of diaphragm muscles.

[0072] FIG. 8A shows H&E staining images of diaphragm muscle sections of WT and mdx4cvmice treated with or without AAV (n = 5 per group; 10 weeks of age); scale bar= 50 pm.

[0073] FIG. 8B is a bar graph showing quantification of CNF in diaphragm muscles of 10- week-old mdx4cvmice with or without AAV treatment (n=5 each, two-tailed unpaired t test).

[0074] FIG. 8C shows Masson’s Trichrome staining images of diaphragm muscle sections ofWT and mdx4cvmice treated with or without AAV (n = 3 per group; 10 weeks of age); scale bar=50 μm.

[0075] FIG. 8D is a bar graph showing quantification of percentage fibrotic area in diaphragm muscles of 10-week-old WT and mdx4cvmice treated with or without AAV (n = 3 per group, one- way ANOVA with Turkey’s multiple comparisons test for three groups).

[0076] FIG. 9 A shows a Western blotting analysis of dystrophin expression in HEK293 cells transfected with or without different versions of Dys-N, M, and C constructs at specified molar ratios. HEK293 cell lysate transfected with a full length (FL)-dystrophin construct was used as a positive control (pXL780) and GAPDH was used as a loading control.

[0077] FIG. 9B, 9C, and 9D are bar graphs showing densitometry quantification of the FL- dystrophin band density of FIG 9A.

[0078] FIG. 10A shows a Western blotting analysis of dystrophin expression in HEK293 cells transfected with or without different versions of Dys-N, M, and C constructs at specified molar ratios. HEK293 cell lysate transfected with a full length (FL)-dystrophin construct was used as a positive control (pXL780) and GAPDH was used as a loading control.

[0079] FIG. 10B, 10C, and 10D are bar graphs showing densitometry quantification of theFL-dystrophin band density of FIG 10A.

[0080] FIG. 11A is a diagram showing the strategies to increase FL-dystrophin assembly by eliminating the PB29 fusion tag on the C construct or by changing the split intein between M andC Constructs.

[0081] FIG. 11B shows Western blotting analysis of dystrophin expression in HEK293 cells transfected with or without different versions of Dys-N, M, and C at the specified amounts of plasmids (μg). HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control (FL l.Oμg) and the GAPDH was used a loading control.

[0082] FIG. 11C, 11D, and HE are bar graphs showing densitometry quantification of theFL-dystrophin band density of FIG 11B.

[0083] FIG. 12A is a diagram showing the strategies to increase FL-dystrophin assembly by eliminating the PB29 fusion tag on the C construct or by changing the junctional sequence of theC construct.

[0084] FIG. 12B shows Western blotting analysis of dystrophin expression in HEK293 cells transfected with or without different versions of Dys-N, M, and C at the specified amounts of plasmids (μg). HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control (FL l.Oμg) and the GAPDH was used a loading control.

[0085] FIG. 12C, 12D, and 12E are bar graphs showing densitometry quantification of theFL-dystrophin band density of FIG 12B.

[0086] FIG. 13A and 13B are immunofluorescent images of muscle sections from wildtype and mdx4cv mice treated with or without ZD101 (10 weeks of age, n=5 per group), stained with two different anti-dystrophin antibodies recognizing N and C fragments, respectfully.

[0087] FIG. 14A is a graph depicting measurements of serum creatine kinase (CK) levels in8-week-old mice (n = 4 WT, 9 mdx4cv, 8 mdx4cv / FL, 5 mdx4cvμ -, 8 mdx4cv / ZD 101 , 9 weeks of age)FL, the triple vector FL-dystrophin at 2E+14 vg / kg (molar ratio: 2:2: 1); μ, micro-dystrophin at8E+13 vg / kg; ZD101, the improved triple vector FL-dystrophin (ZD101) at 2E+14 vg / kg (molar ratio: 1 :1 :1).

[0088] FIG. 14B is a graph depicting Tetanic torque measurements of the posterior compartment muscles of the mice8-13 weeks of age). FL, the triple vector FL-dystrophin at 2E+14 vg / kg (molar ratio: 2:2: 1); μ, micro-dystrophin at 8E+13 vg / kg; ZD101, the improved triple vector FL-dystrophin (ZD101) at2E+14 vg / kg (molar ratio: 1 : 1 : 1).

[0089] FIG. 14C is a graph depicting measurements of the hanging time before the mice fell from the wire mesh (weeks of age). FL, the triple vector FL-dystrophin at 2E+14 vg / kg (molar ratio: 2:2: 1); p, micro-dystrophin at 8E+13 vg / kg; ZD 101, the improved triple vector FL-dystrophin (ZD 101) at 2E+14 vg / kg (molar ratio: 1 :1 :1).

[0090] FIG. 15A is a diagraph of various utrophin-dystrophin chimeras.

[0091] FIG. 15B is a graph depicting measurements of serum creatine kinase (CK) levels in miceage).

[0092] FIG. 15C is a graph depicting Tetanic torque measurements of the posterior compartment muscles of the mice

[0093] FIG. 16A is a diagram showing the N and C constructs for dual vector assembly of near-full-length (NFL) dystrophin.

[0094] FIG. 16B show Western blot analysis of dystrophin expression in HEK293 cells transfected with different versions of Dys-N and C constructs at the specified amounts of plasmids(μg). HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control(pXL780 l .Oμg) and the GAPDH was used a loading control.

[0095] FIG. 16C are bar graphs showing densitometry quantification of the FL dystrophin band intensity of FIG. 16B.

[0096] FIG. 17A is a diagram showing different strategies to deliver NFL-dystrophin using dual vectors.

[0097] FIG. 17B shows Western blot analysis of dystrophin expression in HEK293 cells transfected with or without different versions of dual constructs at the specified amounts of plasmids (μg). HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control (pXL780 l.Oμg) and the GAPDH was used a loading control.

[0098] FIG. 17C are bar graphs showing densitometry quantification of the FL dystrophin band intensity of FIG. 17B.

[0099] FIG. 18A is a diagram showing different strategies to enhance split intein-mediated protein trans-splicing by adding a coil domain SARAH.

[0100] FIG. 18B shows Western blot analysis of dystrophin expression in HEK293 cells transfected with different versions of Dys-N and C constructs at the specified amounts of plasmids(μg). HEK293 cell lysate transfected with a FL-dystrophin construct was used as a positive control(pXL780 l.Oμg) and the GAPDH was used a loading control.

[0101] FIG. 18C are bar graphs showing densitometry quantification of the FL dystrophin band intensity of FIG. 18B.DETAILED DESCRIPTION

[0102] The DMD gene provides instructions for making dystrophin proteins that belong to the spectrin superfamily of cytoskeletal proteins. The major isoform expressed in striated muscles is a 427 kDa protein, containing four main domains: an N-terminal actin-binding domain, a long rod- like domain composed of spectrin-like repeats, a cysteine-rich domain that binds to dystroglycanand other membrane-associated proteins, and a C-terminal domain that interacts with syntrophin and a-dystrobrevin, forming a large dystrophin-gly coprotein complex with these proteins and(DGC). See, e.g., Ervasti et al., Cell 1991;66: 1121-1131 and Ohlendieck et al., J Cell Biol1991;112: 135-148. The DGC links the actin cytoskeleton to the extracellular matrix, facilitating force transmission, providing mechanical stability and protection to the muscle fiber membrane. protection, and mediating signal transduction. See, e.g., Cohn & Campbell, Muscle Nerve 2000;23:1456-1471; Han et al., Proceedings of the National Academy of Sciences of the United States ofAmerica 2009;106: 12573-12579; and Olthoff et al., Nature Communications 2018;9:5104.Disrupted expression of dystrophin leads to repeated cycles of muscle damage and repair, which exhausts the regenerative capacity of muscle stem cells and leads to progressive loss of muscle mass and function of skeletal, cardiac, and respiratory muscles, the consequences of which include impaired mobility, cardiomyopathy, respiratory failure, and early death. See, e.g., Muntoni et al.,Curr Opin Neurol 2003;16, 577-583 and Spurney, Muscle Nerve 2011;44:8-19. Duchenne muscular dystrophy (DMD) is one example of a fatal genetic disease caused by genetic mutations in the DMD gene located on the X chromosome, which result in disrupted expression of dystrophin proteins and deficiency thereof.

[0103] A gene replacement therapy employing a vector, such as a viral vector to deliver a fulllength of the DMD gene could, in theory, allow the restoration of dystrophin to halt / reverse the deterioration of muscles. See, e.g., Mullard et al., Nat Rev Drug Discov 2023;22:610. However, the limited cargo capacity of viral vectors, such as the approximate 4.5 kb capacity of an adeno- associated viral (AAV), makes it challenging to deliver the full-length DMD gene, the cDNA of which has a size in excess of 11 kb. Early studies found that patients carrying a large internal deletion of the DMD gene developed a mild form of the disease, Becker muscular dystrophy(BMD), owing to the expression of truncated but partially functional dystrophin proteins. See, e.g.,England et al., Nature 1990;343:180-182. These findings led to the development of microdystrophins (μDys) gene therapy, which aims to restore the expression of a truncated version of the dystrophin protein. See, e.g., Banks et al., PLoS Genetics 2010;6, el000958; Gregorevic et al.,Nature Medicine 2006;12:787-789; and Ramos et al., Molecular Therapy: The Journal of theAmerican Society of Gene Therapy 2019;27, 623-635. These miniaturized forms of dystrophin are only about 1 / 3 of the full-length dystrophin with some of the essential functional domains of the protein retained and able to fit into one AAV vector for in vivo delivery, thereby restoring muscle integrity and improving muscle function. See, e.g., Gregorevic et al., Nature Medicine2006;12:787-789;Ramos et al., Molecular Therapy: The Journal of the American Society of GeneTherapy 2019;27, 623-635; and Birch et al., Sci Transl Med 2023, '15, eabol815.

[0104] Recently, the US Food and Drug Administration (FDA) granted the accelerated approval to Sarepta’s Elevidys (μDys delivered in AAVrh.74) for DMD patients at 4 to 5 years of age. See, e.g., Hoy, Drugs 2023;83, 1323-1329. However, due to the lack of 2 / 3 of the dystrophin coding sequence containing critical rod and hinge domains of dystrophin needed to connect with other proteins in the dystrophin complex, these μDys gene therapies could not offer full protection of skeletal and heart muscle integrity and function. Indeed, Elevidys failed to produce a statistically significant improvement in the North Star Ambulatory Assessment (NSAA) as compared to placebo after 52 weeks of treatment, highlighting the urgent need to develop novel strategies to deliver full-length dystrophin. Herein, a “functional” dystrophin protein interacts with other proteins in the dystrophin complex, such as described by Gao & McNally, Compr Physiol. 2015Jul 1;5(3): 1223-39 and Valera et al., Adv Med Sci. 2021 Mar;66(l):52-71.

[0105] Large genes, such as DMD, can be separated across multiple vectors to facilitate gene expression, utilizing a split-gene or split-vector strategy. Several different approaches have been explored using dual AAV vectors to deliver larger payloads, including fragmented genome assembly, overlapping, trans-splicing, and hybrid approaches. However, multiple- or split-vector approaches are associated with certain drawbacks, including low reconstitution efficiency, production of alien proteins, and limited flexibility in split site selection. See, e.g., Riedmayr et al., Nat Commun 2023(14): 6578; Li et al., Hum Gene Ther. 2008 Sep;19(9):958-64; Tolmachov,Med Hypotheses. 2014 Aug;83(2):211-6.

[0106] In one example, two vectors containing an overlapping fragment to express large transgenes may undergo homologous recombination. See, e.g., Halbert et al., NatureBiotechnology 2022;20:697-701; Odom et al., Molecular Therapy: The Journal of the AmericanSociety of Gene Therapy 2011 ; 19:36-45; Sondergaard et al., Ann Clin Transl Neurol 2015;2:256-270; and Pryadkina et al., Molecular Therapy. Methods & Clinical Development 2015;2: 15009.Upon co-delivery, the efficiency of homologous recombination is however a limiting factor for this strategy. Another approach known as trans-splicing is to take advantage of the natural concatamerization ability of AAV to expand the transgene size using dual AAV vectors. See, e.g.,Duan et al., Nature Medicine 2000;6:595-598 and Van et al., Proc Natl Acad Set USA2000;97:6716-6721. However, the head-to-tail concatamer formation and the trans-splicing of the pre-mRNA across the ITR junction pose rate-limiting steps. These approaches may be combined as shown for hybrid vector systems. See, e.g., Ghosh et al., Molecular Therapy: The Journal of the American Society of Gene Therapy 2008; 16: 124-130. Despite the varying success of these dualAAV vector strategies in preclinical studies, the efficiency of expression from the available dualvector systems is insufficient for many clinical gene therapy applications. It is even morechallenging to deliver the FL dystrophin sequence, which is about three times the packaging capacity of AAV, thus requiring at least three vectors to package the entire coding sequence.

[0107] In another example, triple trans-splicing of full-length dystrophin across AAV vectors was explored for in vivo delivery in a study by Koo et al., which showed the feasibility of expressing FL dystrophin, albeit with only very low efficiency (Koo et al., Hum Gene Ther. 2014Feb;25(2):98-108). Koo et al.’s approach involved trans-splicing the full-length protein by cojoining three vectors via their inverted terminal repeat sequences. However, triple trans-splicingAAVs delivering full-length dystrophin was not efficient and unable to show therapeutical levels of expression.

[0108] Protein trans-splicing can be mediated by intein, a protein segment capable of excising itself and joining the remaining portions (the exteins) with a peptide bond during protein splicing, which may expand the delivery capacity of viral vectors used in gene therapy, such as adeno- associated viral (AAV) vectors. See, e.g., Tornabene et al., Sci Transl Med. 2019 May 15; 11(492): eaav4523. Split inteins are small polypeptides that self-assemble and undergo a protein trans- splicing (PTS) reaction, resulting in the formation of a mature, fully functional protein in a“traceless manner.” In vivo delivery of oversized base editors in dual AAV vectors has been accomplished using the split intein strategy. See, e.g., Xu et al., Nature Communications2021;12:371928-30; Zuo et al., CellBiosci 2023;13: 109; and Levy et al., Nat Biomed Eng 2020 .497-110. Applying a split-intein strategy surprisingly facilitated development of a triple AAV system with orthogonal split inteins to deliver FL dystrophin protein packaged into an engineered myotropic AAV capsid (MyoAAV4A), as described, e.g., by Tabebordbar et al., Cell2021;184:4919-4938 e4922. This triple vector combination restored the expression of FLdystrophin and conferred a dramatic improvement in muscle histopathology and function in a mouse model of DMD.

[0109] In one aspect, disclosed herein is a split-gene or split-vector system to facilitate production of a non-truncated, fully functional dystrophin protein in a host cell, such as by protein trans-splicing. Specifically, an exemplary triple vector system was developed to deliver full-length dystrophin (FL-dystrophin) into skeletal and cardiac muscles. Triple vector or triple plasmid systems, such as involving adeno-associated viral-mediated gene therapy, have been described, e.g., by US 2021 / 0275614 Al and WO 2023 / 018854 A2.

[0110] Regarding disclosed polynucleotides and expression systems, FL-dystrophin was split into three fragments (N, M and C) linked to two orthogonal pairs of split intein, allowing efficient, uni -directional assemble of FL-dystrophin. Structurally, the dystrophin protein consists of an N- terminal actin-binding domain (ABDI), 24 spectrin-like repeats that form the rod domain and house the second actin-binding domain (ABD2), and a C-terminal region containing a cysteine- rich domain that binds the dystroglycan complex. The N- and C-terminal ends of the protein provide insight into the mechanism of how the protein can link the costameric F-actin network to both the sarcolemmal membrane and extracellular matrix via the dystroglycan complex. This location in the cytoskeletal network of muscle is crucial for maintaining membrane and costamere integrity, a fact that is best appreciated in the context of Duchenne and Becker muscular dystrophies. In Duchenne and Becker muscular dystrophies, a variety of dystrophin gene mutations, including missense and nonsense mutations, lead to the development of muscle tissue degeneration. Dystrophin gene mutations and the structure of the dystrophin protein have been described, e.g., by Koenig et al., Cell. 1988;53:219-228; Fealey et al., Biophys J. 2018 Aug 7;115(3): 445-454; and Gao & McNally, Compr Physiol. 2015 Jul 1 ;5(3): 1223-39.

[0111] The three fragments packaged into the myotropic AAV capsid of MyoAAV4A restoredFL-dystrophin expression in both skeletal and cardiac muscles in a mouse model of Duchenne muscular dystrophy. Dystrophin-glycoprotein complex components were also restored in the sarcolemma of dystrophic muscles. Muscle histopathology, contractility and overall strength were all significantly improved following MyoAAV4A gene delivery, promoting the viability of the approach to treat conditions characterized by disrupted DMD expression and dystrophin protein deficiency.

[0112] Effective restoration of dystrophin or treatment dystrophin deficiency in accordance with this disclosure can be determined according to methods known to one of skill in the art. In some instances, the improvement in muscle function is an improvement in muscle strength. The improvement in muscle strength is determined by techniques known in the art such as the wire hang test or maximal voluntary isometric contraction testing (MVICT). In some instances, the improvement in muscle function is an improvement in stability in standing and walking. The improvement in stability strength is determined by techniques known in the art such as the 6- minute walk test (6MWT) or timed stair climb. Methods for monitoring, diagnosing, and prognosing muscular dystrophies are also described, e.g, by US 2013 / 0065242 Al and WO2015 / 104403 Al.

[0113] I. Polynucleotides

[0114] In some aspects, provided herein are polynucleotides, such as polynucleotides encoding a full-length dystrophin protein and fragments thereof. Reference to sequence identification numbers, such as the SEQ IDs provided in the Sequence Listing is meant to reference the entire length of the sequence. For example, reference to a polynucleotide having 90% sequence identityto SEQ ID NO:3 is meant to be interpreted as a polynucleotide having 90% sequence identity to the entire length of SEQ ID NO:3.

[0115] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 3, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 3, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 3, or the complement thereof.

[0116] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 5, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 5, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 5, or the complement thereof.

[0117] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 7, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 7, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 7, or the complement thereof.

[0118] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 9, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 9, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 9, or the complement thereof.

[0119] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 11, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 11, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 11, or the complement thereof.

[0120] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 13, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 13, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 13, or the complement thereof.

[0121] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 15, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 15, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 15, or the complement thereof.

[0122] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 17, or thecomplement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 17, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 17, or the complement thereof

[0123] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 19, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 19, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 19, or the complement thereof.

[0124] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 21, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 21, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 21, or the complement thereof.

[0125] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 37, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 371, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 37, or the complement thereof.

[0126] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 39, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 39, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 39, or the complement thereof.

[0127] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 41, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 41, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 41, or the complement thereof.

[0128] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 43, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 43, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 43, or the complement thereof.

[0129] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 45, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotidesequence of SEQ ID NO: 45, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 45, or the complement thereof.

[0130] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 47, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 47, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 47, or the complement thereof.

[0131] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 49, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 49, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 49, or the complement thereof.

[0132] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 51, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 51, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 51, or the complement thereof.

[0133] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 53, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 53, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 53, or the complement thereof.

[0134] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 55, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 55, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 55, or the complement thereof.

[0135] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 57, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 57, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 57, or the complement thereof.

[0136] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 59, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 59, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 59, or the complement thereof.

[0137] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 61, or thecomplement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 61, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 61, or the complement thereof

[0138] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 63, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 63, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 63, or the complement thereof.

[0139] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 65, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 65, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 65, or the complement thereof.

[0140] In some embodiments, a disclosed polynucleotide comprises at least 80%, 85%, 90%,95%, 97%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 67, or the complement thereof. In some embodiments, a disclosed polynucleotide comprises about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 67, or the complement thereof. In some embodiments, a disclosed polynucleotide consists of the nucleotide sequence of SEQ ID NO: 67, or the complement thereof.

[0141] In some embodiments, expression of disclosed polynucleotides yields a dystrophin N fragment (Dys-N) that comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%,97%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 4, SEQ ID NO:38,SEQ ID NO:40, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:64, SEQ ID NO:66, or SEQ IDNO:68.

[0142] In some embodiments, expression of disclosed polynucleotides yields a dystrophin M fragment (Dys-M) that comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%,97%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 10,SEQ ID NO:20, SEQ ID NO:42, or SEQ ID NO:52.

[0143] In some embodiments, expression of disclosed polynucleotides yields a dystrophin C fragment (Dys-C) that comprises an amino acid sequence that has at least 80%, 85%, 90%, 95%,97%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 12,SEQ ID NO: 14, SEQ ID NO:16, SEQ ID NO:18, or SEQ ID NO:22, SEQ ID NO:47, SEQ IDNO:59, or SEQ ID NO:61.

[0144] In some embodiments, expression of disclosed polynucleotides yields a full-length human dystrophin protein, such as a protein comprising at least 80%, 85%, 90%, 95%, 97%, or99% sequence identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the full-length human dystrophin protein comprises about 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the full-length human dystrophin protein consists of the amino acid sequence of SEQ ID NO: 2.

[0145] II. Expression Systems

[0146] In some aspects, provided herein are expression systems, such as split-gene or splitvector expression systems, which produce a full-length dystrophin protein by intein-mediated splicing. The split-gene or split-vector systems disclosed herein may also be interchangeably referred to as multiple gene or multiple vector systems. In some embodiments, disclosed expression systems comprise at least two, at least three, or at least four independent vectors comprising nucleotide sequences which encode fragments of a full-length dystrophin protein. In some embodiments, disclosed expression systems comprise up to two, up to three, up to five, or up to seven independent vectors comprising nucleotide sequences which encode fragments of a full-length dystrophin protein.

[0147] In some embodiments, disclosed expression systems comprise three independent vectors, which each comprise a nucleotide sequence that encodes a fragment of a full-length dystrophin protein. The fragments are joined together by fusion of split inteins in a tripletransplicing approach. In some embodiments, disclosed expression systems comprise three independent vectors, where each independent vector comprises a nucleotide sequence encoding anN, M, or C dystrophin fragment. In some embodiments, SEQ ID NO:3 or the complement thereof encodes a dystrophin N fragment. In some embodiments, SEQ ID NO: 5, SEQ ID NO: 9, SEQID NO: 19, or the complement thereof encode a dystrophin M fragment. In some embodiments,SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ IDNO: 21, or the complement thereof encode a dystrophin C fragment.

[0148] In some embodiments, the amino acid sequence of the full-length dystrophin protein comprises at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the amino acid sequence of the full-length dystrophin protein comprises about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the amino acid sequence of the full-length dystrophin protein consists of the amino acid sequence ofSEQ ID NO:2.

[0149] In some embodiments, disclosed expression systems comprise two independent vectors, which each comprise a nucleotide sequence that encodes a fragment of a near full-length dystrophin protein. The fragments are joined together by fusion of split inteins in a dual- transplicing approach. In some embodiments, disclosed expression systems comprise two independent vectors, where the first independent vector comprises a nucleotide sequence encodingN and M and the second independent vector comprises a nucleotide sequence encoding C dystrophin fragment. In some embodiments, SEQ ID NO:43, SEQ ID NO:55, SEQ ID NO:57,SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67 or the complement thereof encodes a dystrophinN and M fragments. In some embodiments, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 61, or the complement thereof encode a dystrophin C fragment.

[0150] Inteins can be described as protein introns, which are able to auto-catalytically splice themselves out of a protein post-translationally, resulting in covalently linked exteins as a scar less gene product. This process may be termed protein splicing or trans-splicing. Exteins are the remaining portions of the protein after the intein has excised itself out.

[0151] An intein is capable of ligating the first and the second fragment of a protein, a process referred to as intein-mediated protein splicing or intein-mediated trans-splicing. Intein-mediated protein splicing typically occurs after the intein-containing mRNA has been translated into a protein. The process begins with an N — O or N- S shift, when the side chain of the first residue(preferably a serine, threonine, or cysteine) of the (N-terminal split) intein portion of the expression product of the specific splice product nucleophilically attacks the peptide bond of the residueimmediately upstream, i.e., the final residue of the N-extein, to form a linear ester or thioester intermediate. A transesterification occurs when the side chain of the first residue of the C-extein, i.e., the amino acid C-terminal to the C -terminal split intein, attacks the newly formed (thio)ester to free the N-terminal end of the intein. This forms a branched intermediate, in which the N-extein and C-extein are attached, albeit not through a peptide bond. For explanatory purposes, the last residue of the intein can be asparagine, and the amide nitrogen atom of this side chain might cleave apart the peptide bond between the intein and the C-extein, resulting in a free intein segment with a terminal cyclic imide. Finally, the free amino group of the C-extein may now attack the(thio)ester linking the N- and C-exteins together. An O — N or S — N shift therefore preferably produces a peptide bond and the functional, ligated protein.

[0152] As soon as the N- and C-exteins flanking the intein are in spatial proximity to each other, the excision process can be initialized by forming a succinimide intermediate. For this process, the presence of several amino acids in fixed positions may be required. Either a cysteine or a serine residue at the N-terminal side of the intein, an asparagine at the C -terminal side of the intein and another cysteine at the beginning of the C-terminal extein may exist. After splicing has taken place, the resulting protein contains the N-extein linked to the C-extein. This splicing product may be also termed an extein. The ligation activity of an intein can be determined by a person skilled in the art, e.g. by using Western blot for protein detection.

[0153] As used herein a “split intein” describes a subset of inteins that are expressed in two separate fragments or alternatively an “N-intein” fragment and a “C-intein” fragment, e.g., Cfa-N and Cfa-C represented by SEQ ID NO:31 and SEQ ID NO:32, respectively, Gp41-1-N and Gp41-1-C represented by SEQ ID NO:33 and SEQ ID NO:34, respectively, and IMPDH-l-N andIMPDH-l-C represented by SEQ ID NO:35 and SEQ ID NO:36, respectively, which catalyzetrans-splicing upon association of the two domains. The split intein may occur naturally and may also been artificially generated by splitting of a contiguous intein. With their unique properties, split-inteins offer improved controllability, flexibility and capability to existing tools based on contiguous inteins. Examples of split inteins include the Npu intein, the NrdJ-1 intein, the CFA intein, the IMPDH-1 intein, or the gp41-l intein. See, e.g., US 2023 / 0024301 Al.

[0154] In some embodiments, a dystrophin N protein fragment is joined to a dystrophin M protein fragment by split intein CFA, GP41-1, or IMPDH-1. In some embodiments, a dystrophinM protein fragment is joined to a dystrophin C protein fragment by split intein CFA, GP41-1, orIMPDH-1. In some embodiments, a dystrophin N protein fragment is joined to a dystrophin M protein fragment by split intein CFA, such as joined by CFA-N and CFA-C fragments, e.g., as represented by SEQ ID NO:31 and SEQ ID NO:32. In some embodiments, a dystrophin M protein fragment is joined to a dystrophin C protein fragment by split intein IMPDH-1, such as joined by IMPDH-l-N and IMPDH-l-C fragments, e.g., as represented by SEQ ID NO:35 andSEQ ID NO:36

[0155] In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO: 3, or the complement thereof. In some embodiments, a disclosed expression system comprises a nucleotide sequence that has about 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 3, or the complement thereof.

[0156] In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof. In someembodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof.

[0157] In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO:17, SEQ ID NO: 21, or the complement thereof. In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO:17, SEQ ID NO: 21, or the complement thereof.

[0158] In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45,SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ IDNO:57, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, or the complement thereof. In some embodiments, a disclosed expression system comprises an independent vector comprising a nucleotide sequence that has about 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the nucleotide sequence of SEQ IDNO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47,SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ IDNO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, or the complement thereof.

[0159] In some embodiments, a disclosed expression system further comprises one or more regulatory elements, such as an element that regulates the expression of a nucleotide sequence encoding an N, M, or C dystrophin fragment as disclosed herein. In some embodiments, disclosed expression systems further comprise a promoter, such as a promoter that is operably linked to a nucleotide sequence encoding a fragment of a full-length dystrophin protein, e.g., an N, an M, or a C dystrophin fragment as disclosed herein. In some embodiments, the promoter is a cytomegalovirus (CMV), Spc5-12 promoter, Spc2-26 promoter, muscle creatine kinase (MCK), dMCK, tMCK, desmin (Des), alpha-myosin heavy chain (α-MHC), myosin light chain 2 (MLC-2), cardiac troponin C (cTnC) or slow isoform of troponin I (TnIS). In preferred embodiments, the promoter is a muscle specific gene promoter such as Spc5-12, Spc2-26, muscle creatine kinase(MCK), dMCK, tMCK, desmin (Des), alpha-myosin heavy chain (α-MHC), myosin light chain 2(MLC-2), cardiac troponin C (cTnC), or slow isoform of troponin I (TnIS).

[0160] In some embodiments, the promoter comprises a cardiac specific promotor. In other embodiments, a non-specific promoter is used. In some embodiments, the promoter is selected from CMV, mini-CMV, CBA, HSV, TK, RSV, SV40, MMTV, Ad El A, cardiac troponin C, cardiac troponin I, cardiac troponin T (cTnT), and combinations thereof.

[0161] In some embodiments, a disclosed expression system comprises a promoter that has at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:24, SEQ ID NO:26, SEQ IDNO:27, or the complement thereof. In some embodiments, a disclosed expression system comprises a promoter that has about 85%, 90%, 95%, 99%, or 100% sequence identity to SEQ IDNO:24, SEQ ID NO:26, SEQ ID NO:27, or the complement thereof.

[0162] In some embodiments, a disclosed expression system comprises multiple promoters. In some embodiments, the promoters are the same. In some embodiments, the promoters are different.In some embodiments, a disclosed expression system comprises an enhancer sequence, such as a tissue specific enhancer, which imparts muscle-specific expression on the gene of interest, such asN, M, and C dystrophin fragments. In some embodiments, a disclosed expression system comprises a muscle-specific enhancer. In some embodiments, the muscle-specific enhancer is a muscle creatine kinase enhancer, a myo D enhancer, a myosin enhancer, an actin enhancer, and orthologs thereof.

[0163] In some embodiments, a disclosed expression system comprises an enhancer element, such as a muscle creatine kinase enhancer, that has at least 85%, 90%, 95%, or 99% sequence identity to SEQ ID NO:25. In some embodiments, a disclosed expression system comprises an enhancer element, such as a muscle creatine kinase enhancer, that has about 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQID NO:25.

[0164] In some embodiments, a disclosed expression system comprises one or more polyA signals. In some embodiments, a polyA signal is positioned upstream of the start codon in a disclosed expression system. In some embodiments, independent vectors in a disclosed expression system comprise a polyA signal. The polyA signal can be the same or different among the independent vectors. In some embodiments, a disclosed expression system comprises a polyA signal, such as a mini-polyA signal, that has at least 85%, 90%, 95%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO:23. In some embodiments, a disclosed expression system comprises a polyA signal, such as a mini-polyA signal, that has about 92%, 95%, 97%, 99%, or100% sequence identity to SEQ ID NO:23.

[0165] In some embodiments, a disclosed expression system comprises a Kozak sequence. AKozak sequence is a functional sequence motif that is recognised by a ribosome as the translational start site and is positioned near or at the translational initiation site of eukaryotic mRNAs. Kozak sequences mediate ribosome assembly and regulate translation initiation, ensuring protein translated in the correct reading frame. In some examples, the Kozak sequence includes the ATG initiation (start) codon in DNA (AUG in mRNA). The exact Kozak sequence present in eukaryotic mRNA determines the efficiency of translation initiation, i.e., certain Kozak sequences will not lead to efficient translation initiation.

[0166] In some embodiments, a disclosed expression system comprises a Kozak sequence that has about 56%, 67%, 77%, 89%, or 100% sequence identity to the nucleotide sequence of SEQID NO:28 or SEQ ID NO:29 In some embodiments, a disclosed expression system comprises aKozak sequence that consists of SEQ ID NO:28 or SEQ ID NO:29. In some embodiments, theKozak sequence is non-native to one or more of the transgene, such as the nucleotide sequence encoding the dystrophin protein fragment, any enhancer element and / or the promoter.

[0167] In some embodiments, disclosed expression systems comprise a degradation signal. In some embodiments, the degradation signal is the short degron CL1, a C-terminal destabilizing peptide that shares structural similarities with misfolded proteins, which is recognized by the ubiquitination system. See, e.g., Gilon et al., The EMBO Journal 1998; 17: 2759-2766 and Bence et al., Science. 2001;292: 1552-1555. In some embodiments, the degradation signal is ubiquitin, whose fusion at the N-terminal of a donor protein mediates both direct protein degradation or degradation via the N-end rule pathway. See, e.g., Bachmair et al., Science 1986;234:179-186 andJohnson et al. The EMBO Journal. 1992;11 : 497-505. In some embodiments, the degradation signal is an N-terminal PB29 degron, such as a peptide which, similarly to the CL1 degron, ispredicted to fold in structures that are recognized by enzymes of the ubi quid nation pathway. See, e.g., Sadis et a\., Molecular and Cellular Biology .1995;15:4086-4094. In some embodiments, the degradation signal is a PB29 signal, such as encoded by a nucleotide sequence that has about 64%,73%, 82%, 91%, or 100% sequence identity to SEQ ID NO:30, or the complement thereof.

[0168] In some embodiments, disclosed expression systems comprise the genome of a viral vector. In some embodiments, the viral vector comprises an adeno-associated virus (AAV) vector genome, such as a recombinant adeno-associated virus vector genome. In some embodiments, the genome is a single- stranded or self- complementary AAV nucleic acid vector. In some embodiments, there is provided a plurality of AAV vectors comprising one or more of the nucleic acid sequences disclosed herein. In some embodiments, the plurality of vectors comprises at least one myotropic AAV vector (myoAAV). In some embodiments, the plurality of vectors comprises or consists of one, two, or three myotropic AAV vector(s) (myoAAV).

[0169] Exemplary myotropic AAV vectors include AAV vector capsids with high tropism towards skeletal muscle and heart, e.g., MyoAAV2A, MyoAAV4A, and AAVmyo. For example, such myotropic AAV capsids have been described in libraries of AAV capsids containing seven random amino acid insertions into the variable region VIII of AAV9 and in vivo. See, e.g.,Tabebordbar et al., Cell 2021;184, 4919-4938 e4922, Weinmann et al., Nature Communications2020; 11 :5432, and El Andari et al., Science Advances 2022;8, eabn470442. These newly engineered myotropic AAV capsids share a common “RGD” motif, which is known to bind to several integrin heterodimers, e.g., as described by Ruoslahti, Annu Rev Cell Dev Biol1996;12:697-715. Additional exemplary MyoAAV vectors and associated capsids are described, e.g., by Liu et al., Hum Gene Ther. 2023 May;34(9-10):350-364 and El Andari et al., SciAdv. 2022Sep 23;8(38):eabn4704.

[0170] In some embodiments, a disclosed expression system comprises, consists of, or consists essentially of a myotropic adeno-associated virus vector, a nucleotide sequence encoding a dystrophin N protein fragment, a dystrophin M protein fragment, or a dystrophin C protein fragment, a promoter, such as a muscle specific promoter, and a Kozak sequence that is non-native(e.g., not normally associated with the expression or function of) with respect to one or more of the dystrophin protein fragments. In some embodiments, an enhancer element is included, such as a muscle creatinine kinase enhancer. In some embodiments, the expression system is flanked on each side, the 5’ end and the 3’ end, by an inverted terminal repeat sequence.

[0171] III. Host Cells

[0172] In some aspects, provided herein are cells, such as host cells, comprising the polynucleotides and expression systems disclosed herein and methods for transducing the cells with the same. In some embodiments, such as in a triple-transplicing approach as described herein, a cell is transduced with equivalent amounts of nucleotide sequences encoding N, M, and C fragments of a full-length dystrophin protein as disclosed herein. Equivalent amount may be represented as a ratio, e.g., 1 :1 :1. In some embodiments, such as in a triple-transplicing approach as described herein, a cell is transduced with different amounts of nucleotide sequences encodingN, M, and C fragments of a full-length dystrophin protein as disclosed herein. Different amounts may also be represented as a ratio, e.g., 2:2:1. Amounts are expressed as vector genomes per kilogram bodyweight (vg / kg).

[0173] In some embodiments, disclosed methods comprise transducing a cell with a disclosed expression system, such as an expression system comprising three independent vectors in equivalent amounts, such as a ratio of 1 : 1: 1, 2:2:2, 3:3:3, 4:4:4, or 5:5:5, etc., where each vectorseparately comprises a nucleotide sequence encoding an N, M, or C dystrophin protein fragment as disclosed herein.

[0174] In some embodiments, disclosed methods comprise transducing a cell with a disclosed expression system, such as an expression system comprising three independent vectors in equivalent amounts, such as a ratio of 1:1:1, 1:1:1.4, 1:1:2, 2:2:1, 3:1:1, 1:2:2, 1:1:2, 2:1:1, 2:2:1,2:1:2, 3:2:1, 1:2:3, 2:1:3, 2:2:3, 3:1:2.3:3:1, 1:3:3, 3:2:2.2:3:2, 2:3:3, 3:2:3, or 3:3:2, etc, where each vector separately comprises a nucleotide sequence encoding an N, M, or C dystrophin protein fragment as disclosed herein.

[0175] In some embodiments, disclosed methods comprise transducing a cell with a disclosed expression system, such as an expression system comprising three independent vectors, where a first independent vector comprises a nucleotide sequence that has at least 85%, 90%, or 95% sequence identity to SEQ ID NO: 3, SEQ ID NO:37, SEQ ID NO:39, or the complement thereof; a second independent vector comprises a nucleotide sequence that has at least 85%, 90%, or 95% sequence identity to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO: 10,SEQ ID NO:20, SEQ ID NO:41, SEQ ID NO:51 SEQ ID NO:53, or the complement thereof; and a third independent vector comprises a nucleotide sequence that has at least 85%, 90%, or 95% to any one of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO:17, SEQ ID NO: 21, SEQ ID NO:47, SEQ ID NO:59, or the complement thereof, and where the cell is transduced with the first, second, and third independent vectors in a vg / kg ratio of 1:1:1,1:1:1.4, 1:1:2, 2:2:1, 3:1:1, 1:2:2, 1:1:2, 2:1:2, 3:2:1, 1:2:3, 2:1:3, 2:2:3, 3:1 :2.3:3:1, 1 :3:3, 3:2:2.2:3:2, 2:3:3, 3:2:3, or 3:3:2.

[0176] In some embodiments, a disclosed cell comprises a first independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity toSEQ ID NO: 3, SEQ ID NO:37, SEQ ID NO:39, or the complement thereof, a second independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO:41,SEQ ID NO:53, or the complement thereof and a third independent vector comprising a nucleotide sequence that has at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO:7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, SEQID NO:59, or the complement thereof.

[0177] In some embodiments, a disclosed cell comprises a protein that has at least 80%, 85%,90%, 95%, 97%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, a disclosed cell comprises a protein that has about 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ IDNO:2.

[0178] In some embodiments, a disclosed cell comprises at least one protein that has at least80%, 85%, 90%, 95%, 97%, or 99% sequence identity to the amino acid sequence of SEQ IDNO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQID NO:16, SEQ ID NO: 18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:38, SEQ ID NO:40,SEQ ID NO:42, SEQ ID NO:54, SEQ ID NO:60, or a combination thereof.

[0179] In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a muscle cell. In some embodiments, the cell is a cardiac muscle cell. In some embodiments, the cell is a skeletal muscle cell. In some embodiments, the cell is a myocyte or a cardiomyocyte. In preferred embodiments, the cell is a human cell.

[0180] In a further aspect, provided herein are pharmaceutical compositions comprising the disclosed polynucleotides, expression systems, host cells, and combinations thereof. In someembodiments, a pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

[0181] IV. Method of Treatment

[0182] In some aspects, provided herein are methods of treating a subject having a condition characterized by disrupted dystrophin gene expression and / or dystrophin protein deficiency. In some embodiments, the method of treatment comprises administering an effective amount of a disclosed polynucleotide, expression system, host cells, pharmaceutical composition, or a combination thereof, to a subject in need thereof, such as a subject having muscular dystrophy.

[0183] Disrupted dystrophin gene expression and / or dystrophin protein deficiency can be determined according to methods available to one of skill in the art. In some example, disrupted dystrophin gene expression and / or dystrophin protein deficiency can be determined by physical examination of a subject, such as blood tests, electrical tests on the nerves and muscles, a muscle biopsy, or combinations thereof. In other examples, disrupted dystrophin gene expression and / or dystrophin protein deficiency can be determined by genetic testing, such as DNA testing.Disrupted dystrophin gene expression and / or dystrophin protein deficiency can be determined by evaluating biomarkers, e.g., creatinine kinase (CK), serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), blood urea nitrogen (BUN), and cardiac Troponin I

[0184] In some embodiments, the condition is a type of muscular dystrophy. In some embodiments, the condition is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy(BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, a limb-girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, or a combination thereof. In some embodiments, the LGMD is any one of alpha-sarcoglycanopathy (LGMD2D), gamma-sarcoglycanopathy (LGMD2C), calpainopathy (LGMD2A), dysferlinopathy, orMiyoshi muscular dystrophy (limb girdle muscular dystrophy R2).

[0185] In some embodiments, the provided method of treatment improves a symptom associated with muscular dystrophy. In some embodiments, the symptom is poor motor control, a vision problem, a breathing issue, muscle degeneration, droopy eyelids, falling, such as frequently falling, difficulty rising from a lying or sitting position, trouble running and jumping, waddling gait, walking on the toes, enlarged calf muscles, muscle pain and stiffness, a learning disability, a cardiac disturbance, such as cardiomyopathy, or a combination thereof.

[0186] Herein, the terms “subject,” and “patient” are used interchangeably. In some embodiments, a subject is a mammal, such as a human, a nonhuman primate, a dog, a cat, a horse, a sheep, a poultry, a cow, a pig, a mouse, a rat, a rodent, or a goat. In preferred embodiments, the subject or the mammal is a human.

[0187] Herein, an “effective amount” of the polynucleotides, expression systems, host cells, and pharmaceutical compositions of the disclosure generally refer to an amount sufficient to elicit the desired biological response, e.g., express the functional, non-truncated dystrophin protein in a target cell, treat Duchenne muscular dystrophy, etc. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent described herein may vary depending on such factors as the condition being treated, the mode of administration, and the age, body composition, and health of the subject. Suitable dosage ranges are readily determinable by one skilled in the art.

[0188] Herein, the terms “treat”, “treating”, “treatment”, and “therapy” encompass an action that occurs while a subject is suffering from a condition which reduces the severity of the condition(or a symptom associated with the condition) or slows the progression of the condition (or a symptom associated with the condition).

[0189] Grammatical variations of “administer,” “administration,” and “administering” to a subject include any route of introducing or delivering to a subject an agent. Administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by implanted reservoir, and the like.EXAMPLES

[0190] Example 1: Proof-of-concept design of split intein constructs to assemble FL- dystrophin

[0191] The cDNA for FL-dystrophin is over 11 kb, about three times of the AAV packaging capacity. Thus, it requires three AAV vectors to package the entire coding sequence of FL- dystrophin. FL-dystrophin cDNA was rationally split into three fragments based on 1) the fragment size, 2) the protein domain structure, and 3) the junctional sequence compatibility for split intein.Applicant chose these two orthogonal pairs of inteins for an initial test, Cfa (e.g., as described byStevens et al., J Am Chem Soc 2016;138:2162-2165) and Gp41-1 (e.g., as described by Carvajal-Vallejos et al., J Biol Chem 2012;287, 28686-28696). The first split site was chosen in between spectrin repeat (SR) 8 and 9, where a cysteine residue is followed by a bulky tryptophan residue as required for efficient protein splicing by the Cfa intein (FIG. 1A). The second split site was chosen within the end of Hinge 3 (H3) domain where two consecutive serine residues are located, which may facilitate protein splicing by the Gp41-1 intein (FIG. 1A). In addition, this is also where the native Dp 140 isoform starts.

[0192] Splitting the full-length dystrophin gene in accordance with these methods resulted in three fragments, an N, an M, and a C fragment. The three fragment constructs of this proof-of-concept expression system were named Dys-Nl, Dys-Ml, and Dys-Cl, respectively. Each expression cassette had a mini-CMV promoter with a muscle creatinine kinase enhancer(meCMV). Transfection of Dys-Nl / Ml / Cl into HEK293 cells resulted in the expression of FL- dystrophin detectable by three different anti-dystrophin antibodies that specifically recognize theN, M or C fragments, respectively (FIG. IB). However, the FL-dystrophin band was much weaker than the unassembled (UA) or partially assembled (PA) dystrophin fragments. Varying the ratio of the three plasmids, such as the vg / kg ratio, improved the relative abundance of the FL versus the unassembled or partially assembled dystrophin signals, with the 4:2:1 ratio of N1 :M1 :C1 plasmids yielding the highest level of FL-dystrophin. Interestingly, the N-terminal fragment band was barely visible, indicating that the assembly between the N and M fragments mediated by Cfa intein was highly efficient. The C-terminal fragment band was much more intense than either theFL or PA M / C bands, indicating that the assembly between the M and C fragments mediated byGp41-1 intein was inefficient.

[0193] Example 2: Optimization of split intein constructs to improve FL-dystrophin assembly

[0194] Further experimentation was conducted to optimize the assembly between M and C fragments. First, we tested a different split site (IGA-SPT) within the H3 domain and mutated the-1 position from alanine to tyrosine to favor the Gp41-1 -mediated PTS, as represented in FIG. 2A.These changes (Dys-M2 and Dys-C2) led to a substantial improvement in the FL-dystrophin assembly, as shown by protein detection in FIGs. 2B and 2C FIGs. 2D, 2E, and 2F show the reduction of unassembled fragments, whereas the decrease in partially assembled fragments is represented in FIGs. 3A-3I. In addition, removal of a small intron within the C fragment construct(Dys-C3) significantly increased the FL-dystrophin assembly band intensity (FIGs. 2B and 2C).

[0195] Next, the +1 to +3 position on the extein, e.g. Dys-C3, was tested for its effects on PTS efficiency. The SPT sequence was mutated to SSS at the junction site on the C fragment construct, as represented by FIG. 2G. Additionally, the strong Kozac sequence was replaced with a weakKozac sequence, considering the abundance of the C fragment. However, these two changes (Dys-C4) led to a substantial reduction of the FL-dystrophin band with an increased accumulation of theNM band and C band, as shown in FIGs 2H, 21, 2J, 2K, 2L and FIGs. 3D-3F. It was reasoned that this may be caused by the use of the weak Kozac sequence, which potentially leads to the translation initiation from a downstream in-frame start codon so that the C fragment was expressed without the intein fusion. After switching the weak Kozac sequence back to a strong one in t C fragment construct Dys-C5, FL-dystrophin expression was restored. See also FIGs 2H, 21, 2J,2K, 2L and FIGs 3D-3F. A synthetic signal for ubiquitin-dependent proteolysis (PB29), e.g., as described by Sadis et al., Mol CellBiol 1995;15:4086-4094, was added to the Dys-C5 construct to lower the expression level of the C fragment. Although the FL-dystrophin band signal was reduced when compared to Dys-C3, we observed that the NM fragment was almost undetectable, indicating that these changes improved NM and C assembly.

[0196] Applicant experimented with a different intein (IMPDH-1), which has a fast PTS rate comparable to Gp41-1 with a native junction sequence of GGG-SIC, e.g., as described by Carvajal-Vallejos et al., J Biol Chem 2012;287:28686-28696, similar to the split site of dystrophin (IGA-SPT) (FIG. 2M). Also, the alanine at the -1 position of Dys-M2 extein to glycine was mutated to further mimic the native junction sequence of IMPDH-1. These changes (Dys-M3 and Dys-C6) significantly improved the FL-dystrophin signal by about 86%, as shown in FIGs. 2N and 20.Moreover, the unassembled C fragment band was dramatically reduced by about 76% as comparedto Dys-Nl / M2 / C5 (FIGs. 2N and 2R), with marginal effects on the unassembled N and M fragments (FIGs. 2N, 2P, and 2Q) and partially assembled fragments shown in FIGs. 3G-3I.

[0197] Two different poly-adenylation signal sequences, described by, e.g., Luo et al., NatBiotechnol. 2024 Jan 2, were inserted at the upstream of the start codon in order to further lower the expression level of the C fragment (Dys-C7 and Dys-C8), as shown in FIG. 4A. These changes significantly reduced the C -fragment band intensity while still maintaining a high level of FL- dystrophin expression. See (FIGs. 4B, 4C, and 4F) and similar N / FL (FIG. 4D) or MC / FL ratio(FIG. 41). However, lowering C-fragment expression further caused a concomitant accumulation of the M and NM fragments, as shown in FIG. 4E and FIGs. 4G and 4H, respectively. These data indicate that some excess of the C-fragment favors the assembly ofFL-dystrophin. Dys-Nl / M3 / C6 was selected for further in vivo studies.

[0198] Example 3: Restoration of FL-dystrophin expression in mdx4cvmice following systemic MyoAAV delivery of Dys-Nl / M3 / C6

[0199] Adeno-associated viral vector capsid MyoAAV4A was used to package dystrophin fragments Nl, M3, and C6. The engineered myotropic adeno-associated viral capsid MyoAAV4A has been described, e.g., by Tabebordbar et al., Cell, 2021 :184, 4919-4938 e4922). For the N andM fragment constructs, the generic promoter meCMV was replaced with synthetic muscle-specific promoter Spc5-12. For the C fragment construct, the generic promoter meCMV was replaced with synthetic muscle-specific promoter Spc2-26. Both muscle-specific promoters are described, e.g., by Li et al., Nature Biotechnology 1999;17:241-245. A total dose of 2E+14 vg / kg AAV vectors consisting of Nl, M3 and C6 at a molar ratio of 2: 1 : 1 was delivered to a cohort of 3-4-week old mdx4cvmice (N=13) via retro-orbital injection, as shown in FIG. 5A.

[0200] FIG. 5B shows immunofluorescence staining using the aforementioned anti- dystrophin antibodies. Dystrophin expression was detected at the sarcolemma of wild-type (WT) gastrocnemius (GA) muscle with each antibody, while GA muscle from mdx4cvmice was negative for any of these antibody stains. Administration of exemplary MyoAAV4A triple vectors delivering Dys-N, Dys-M, and Dys-C in a ratio of 2: 1 : 1 for trans-splicing of a full-length dystrophin protein restored dystrophin expression, as determined by detection of all three dystrophin antibodies. See FIG. 5B. Importantly, dystrophin signals were correctly localized at the sarcolemma without noticeable accumulation in the cytoplasm.

[0201] On average, dystrophin was detected in 83.4 ± 2.7 % muscle fibers (FIG. 5C).Dystrophin expression was also robustly rescued in the cardiac muscles of mdx4cvmice with 78.3± 2.7 % cardiomyocytes being dystrophin positive following AAV administration, as shown inFIGs. 6A and 6C. However, fewer dystrophin+fibers were observed in diaphragm muscles (8.6 ±2.6 %) than in the GA muscles (FIGs. 6B and 6D).

[0202] Western blotting was performed to substantiate these observations further. As shown in FIG. 5D, FL-dystrophin was readily detectable using the three different N-, M- or C-recognizing antibodies in gastrocnemius (GA) muscles from mdx4cvmice treated with AAV-N1 / M3 / C6. Both the N- and M-recognizing antibodies detected mostly the FL-dystrophin signals with weak partially assembled dystrophin fragments, while the unassembled N- or M-fragment was hardly discernable (FIG. 5D). The C-recognizing antibody detected FL-dystrophin and unassembled C- fragment with roughly equal intensities, while the partially assembled MC fragment was almost undetectable (FIG. 5D). FL-dystrophin expression was also readily detectable in the heart muscles of AAV-treated mdx4cvmice (FIG. 6E), but the diaphragm muscle showed a much weaker expression of FL-dystrophin and the C fragment following treatment, as shown in FIG. 6F,potentially indicating weak activity of the Spc2-26 promoter and / or the MyoAAV4A capsid in the diaphragm muscle.

[0203] The loss of dystrophin in dystrophic muscle severely affects the integrity of the entireDGC. See, e.g., Cohn & Campbell, Muscle Nerve 2000;23; 1456-1471; Han et al., Proceedings of the National Academy of Sciences of the United States of America 2009;106:12573-12579; andOlthoff et al., Nature Communications 2018;9: 5104. To test if AAV-N1 / M3 / C6 treatment restores the other components of the DGC in mdx4cvmuscles, Applicant performed immunofluorescence staining with the antibodies against various component of the DGC such as α-sarcoglycan (α-SG), β-SG, α-dystroglycan (α-DG), β-DG, neuronal nitric oxide synthase (nNOS) and α-dystrobrevin(α-DB). As shown in FIG. 5E, the DGC components including α-SG, β-SG, α-DG, β-DG, nNOS and α-DB were all severely reduced at the sarcolemma of GA muscle fibers from mdx4cvmice but were substantially restored by AAV-N1 / M3 / C6 treatment.

[0204] Further improvement in FL-dystrophin assembly was achieved through codon optimization of DysNl and M3. As shown in FIGs. 9 A and 9B, the optimized Dys- optNl / optM3 / C6 combination (pZC501 + 504 + 401) enables the transfection with a desirable ratio of 1 : 1: 1 to achieve similar or increased levels of FL-dystrophin expression to the 4:2: 1 ratio achieved with Dys-Nl / M3 / C6 (pZC288 + 382 + 401). It was noted that in this optimized combination, there was significant un-assembled N and M, indicating that the amount of C may be insufficient at this 1 : 1 : 1 ratio. Therefore, further molar ratios of N, M, and C using the optimized construct combinations were evaluated to achieve optimization. As shown in FTGs. 10A-D, the new optimized Dys-optNl / optM3 / C6 enables the transfection with a reduced amount of total DNA at more favourable ratios of 1 : 1 : 1 to 1 : 1 : 1.4 to achieve similar or increased levels of FL-dystrophin expression to the 4:2: 1 ratio of the N1 / M3 / C6 combination.

[0205] To increase the expression of the C terminus, two strategies were evaluated eliminating the protein degradation signal PB29 in the C construct and modifying the intein between the M and C constructs. These strategies are diagrammed in FIG. 11 A. As shown inFIG. 11B-E, removal of PB29 on the C construct has a negative impact on the FL-dystrophin assembly. Furthermore, increasing the amount of C construct present can increase the FL- dystrophin assembly. It was also observed that the Gp41-1 intein between the M and C constructs appears to be slightly better than the IMPDH intein at this position for the FL-dystrophin assembly.

[0206] Additionally, the impact of the protein degradation signal was evaluated on M and C assembly when the Gp41-1 intein was present. The PB29 fusion tag was added to the optimizedM construct and was added to the C constructs with a Gp41-1 intein. Furthermore, the junctional sequence was modified from SPT to SSS in one of the C constructs. (See diagrams of the strategies at FIG. 12A). As shown in FIG. 12B-E, it was observed that the addition of PB29 on both theGp41-1 -based M and C constructs maintained a high level of the FL-dystrophin assembly at0.5:0.5: 1.0 while significantly reducing the unassembled M and C fragments. The modification of the junctional sequence on the C construct also showed beneficial effects on the assembly, particularly at the 0.7:0.7:0.7 μg transfection.

[0207] Example 4: Functional and histopathological improvement in mdx4cvmice following systemic MyoAAV4A delivery of Dys-Nl / M3 / C6

[0208] Increased muscle injury and reduced muscle force production are the pathological hallmarks ofDMD. To examine if the AAV-N1 / M3 / C6 treatment improves the muscle pathologies in mdx4cvmice, we first measured the serum creatine kinase (CK) levels at five weeks followingAAV administration. FIG. 7A shows that compared to WT mice, mdx4cvanimals showed a dramatic elevation in serum CK (WT: 220.6 ± 109.1, n=14 vs mdx4cv: 3946.0 ± 341.1, n=12;p<0.0001), which was significantly reduced in AAV-treated group (1060.0 ± 229.4, n=13; p<0.0001), suggesting that FL-dystrophin expression reduces muscle injury in dystrophic mice.To test if AAV-N1 / M3 / C6 treatment improves the muscle function, muscle contractility was measured using an in vivo muscle test system described, e.g., by Xu et al., Nature Communications2021; 12:3719; Li et al., Molecular Therapy : The Journal of the American Society of Gene Therapy2023;31 :398-408; and Li et al., Nature Communications 2023; 14: 1785.

[0209] The maximum plantarflexion tetanic torque was measured during supramaximal electric stimulation of the tibial nerve at 150 Hz. As found previously, FIG. 7B shows that mdx4cvmice produced dramatically reduced torque as compared to WT controls (WT: 544.7 ± 9.8, n=8 vs mdx4cv'. 298.2 ± 10.6, n=10; p<0.0001). FIG. 7B also shows that systemic delivery of AAV-N1 / M3 / C6 significantly increased the tetanic torque in mdx4cvmice by —51.7% (452.5 ± 12.0, n=11; p<0.0001). A wire hanging test was also performed to evaluate the overall muscle strength in these mice. The latency to when the animal falls was recorded and compared for the animals in each group. FIG. 7C shows that on average, WT mice stayed on the wire mesh for 251.2 ± 32.4 s, while mdx4cvmice held only for 74.2 ± 24.6 s (n=5 for each group; p=0.0024). Remarkably, AAV-N1 / M3 / C6 treatment completely normalized the hanging time on the wire mesh (248.3 ± 28.4 s; n=5; not significantly different from WT, as shown in FIG. 7C).

[0210] To examine if AAV-N1 / M3 / C6 treatment improves the histopathology of mdx4cvmice,Hematoxylin and Eosin (H&E) staining of skeletal muscle sections from the animals was performed. While WT GA muscle sections showed a normal musculature, mdx4cvmice displayed a typical muscular dystrophy phenotype as evidenced by the presence of central nucleated muscle fibers (CNFs), muscle necrosis and regeneration. These pathologies were substantially ameliorated by AAV-N1 / M3 / C6 administration (FIG. 7D). To further quantify the percentages of CNFs, weperformed immunofluorescence staining of the muscle sections with anti-laminin α2 and 4', 6- diamidino-2-phenylindole (DAPI) (FIG. 7D). The CNFs in the GA muscles of mdx4cvmice were reduced from 58.2 ± 1.7 % to 25.1 ± 1.5 % by AAV-N1 / M3 / C6 treatment, as represented in FIG.7E. Owing to the repeated cycles of degeneration and regeneration, the distribution of muscle fiber size in mdx4cvGA shifted to lower sizes as compared to WT (FIG. 7F), whereas AAV-N1 / M3 / C6 treatment shifted the fiber size distribution towards those of the WT muscles (FIG. 7F). The average cross-sectional area (CSA) of muscle fibers was reduced in mdx4cvmice, which was significantly increased following AAV-N1 / M3 / C6 treatment (FIG. 7G). FIG. 8A indicates thatAAV-N1 / M3 / C6 treatment also improved the histopathology of mdx4cvdiaphragm muscles, but significant changes in CNFs in the diaphragm muscles were not observed, as shown in FIG. 8B.These findings are consistent with the low dystrophin restoration in AAV-treated mdx4cvdiaphragm muscles. To examine the impact of AAV-N1 / M3 / C6 treatment on fibrosis, Masson’sTrichrome staining was performed on muscle sections, which showed that the fibrosis in both GA(FIGs. 7D and 7H) and diaphragm (FIGs. 8C and 8D) muscles of mdx4cvmice was greatly attenuated by AAV-N1 / M3 / C6 treatment.

[0211] Finally, to examine if systemic delivery of AAV-N1 / M3 / C6 causes any overt liver toxicity, the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. As previously shown, the dystrophic mice showed a significant elevation of bothAST and ALT in the serum due to muscle injury (FIGs. 71 and 7 J). In contrast, AAV-N1 / M3 / C6 treatment significantly reduced the serum AST and ALT (FIGs. 71 and 7J), consistent with a significant reduction of muscle injury by the AAV treatment.

[0212] The small packaging capacity of AAV vectors limits gene replacement therapy forDMD and many other diseases. Until now, delivering full-length dystrophin to body-wide muscleshas been unsuccessful. Split intein-mediated PTS was harnessed to develop a triple AAV system for efficient assembly and in vivo delivery of full-length dystrophin. Using the newly engineered myotropic AAV capsid, Applicant achieved systemic full-length dystrophin rescue in both skeletal muscle and heart, which led to significant functional and histopathological improvement in mdx4cvmice.

[0213] Using two orthogonal split inteins (Cfa and Gp41-1 or IMPDH-1) with a very fast rate of PTS, Applicant demonstrated the feasibility of generating FL dystrophin protein in vitro and in vivo. Together, split inteins, the split sites, the addition of a protease-degradation signal, and mutation of junctional amino acids, etc. contributed to improvement of assembly efficiency.

[0214] Exemplary construct N1 / M3 / C6 was shown to achieve -60% of FL-dystrophin protein expression, relative to a plasmid carrying the entire dystrophin cDNA, with very low levels of unassembled or partially assembled products in vitro. Earlier studies with Ssp DnaB split intein to assemble a 6.3-kb Becker-form dystrophin, as described by Li et al., Hum Gene Ther 2008;19,958-964, and factor VIII, as described by Chen et al., Mol Ther 2007;15, 1856-1862, were less efficient. These results showed that the selection of split inteins and split sites on dystrophin (and thus the junctional amino acids) are particularly important for efficient FL-dystrophin assembly.The split site for N and M constructs is in proximity to the natural initiation site of the Dp260 isoform whereas the split site for M and C constructs overlaps with the start site of the Dpl40 isoform. The selection of these split sites may help minimize the potential negative impacts of unassembled C and partially assembled MC fragments.

[0215] The molar ratios for each vector carrying the N, M, and C fragments were initially evaluated in vitro by semi-quantitative assessment of each fragment and the resulting assembly products by Western blotting. In this proof-of-principle study, Applicant utilized a weakerpromoter Spc2-26 to drive the C fragment expression and a stronger Spc5-12 to drive the N andM fragment expression. Additionally, efficient gene replacement therapy for DMD was found to require a potent AAV capsid with strong muscle tropism. In this study, Applicant leveraged the high muscle tropism of MyoAAV4A, which allowed simultaneous administration of three AAV vectors at a total dosage that is currently used in clinical trials for neuromuscular diseases.

[0216] To examine if AAV delivery of the codon optimized constructs for FL dystrophin assembly, as described above, would equate to an improvement in the histopathology of mdx4cvmice, delivery of myoAAV4A-FL dystrophin (ZD101) was administered at a total dose of 2E +14 vg / kg, via IV injection at 3 weeks. ZD101 comprised Dys-N construct pZC503, which is the codon optimized Dys-N + Dys-M construct pZC520 which is the codon optimized DysM withPB29 and the Gp41-1 intein + Dys-C construct pZC523 which is the Dys-C with PB29, the Gp41-1 intein, and the modified SSS junction sequence. The table below shows the full ZD101 arrangement:

[0217] Table 1 : ZD101 pZC0503: pX601-spc5-12-coDMD-N-CfaN pZC0520: pX601-Spc5-12-PB29-DMDopt-Cfa-R9-H3-Gp41-l pZC0523: pX601-Spc5-12-PB29-Gp41-l-H3-end_SSS

[0218] Immunoflourescent images of muscle sections from WT and mdx4cvmice treated with or without ZD101 (10 weeks of age, n=5 per group), stained with two different anti -dy str ophhin antibodies recognizing N and C fragments are shown in FIG. 13A and 13B. As seen through the visual examination of the muscle sections, the systemic delivery of myoAAV4A-FL-dystrophin(ZD101) restored dystrophin expression in skeletal muscles, diaphragm and heart of mdx4cv mice.Additionally, measurement of serum creatin kinase (CK) levels in the mice at 8-weeks (FIG. 14A), tetanic torque measurements of the posterior compartment muscles of the mice (FIG. 14B), and measurement of the hanging time before the mice fell from a wire mesh (FIG. 14C), showed that the systemic delivery of ZD101 improved muscle function and reduced muscle injury in mdx4cvmice.

[0219] Collectively, Applicant’s work addresses an important deficiency of current AAV- based gene replacement therapy for DMD. This novel split intein-mediated assembly coupled with a potent myotropic AAV capsid enables full-length dystrophin restoration and functional and histopathological improvement in dystrophic muscles.

[0220] Example 5: Triple-vector utrophin / dystrophin chimeric gene therapy

[0221] Recent clinical trial data showed that DMD patients with deletions in exon 8-11 developed intense immune responses to different micro-dystrophin gene therapy products. It is believed that these micro-dystrophin constructs carry a strong immunogenic epitope encoded by the exon 8-11. In an effort to mitigate this exon8-l 1 -mediated immune response, an alternative embodiment is a chimeric FL-dystrophin where the corresponding regions of dystrophin are swapped with those of utrophin. We generated different utrophin-dystrophin chimeric vectors and tested their in vivo performance in mdx4cv mice through systemic delivery of myoAAV4A-FL- utrophin / dystrophin chimeric protein (ZD 102). As seen in FIG. 15A and 15B, the data showed that replacing the N vector with the corresponding utrophin N terminus offered the most significant functional improvements in mdx4cvmice.

[0222] Example 6: Dual-vector NFL-dystrophin gene therapy

[0223] In an alternative embodiment, a dual vector approach was tested for assembly of near- full-length (NFL) dystrophin. FIG. 16A shows the N and C constructs to assemble NFL-dystrophin. This approach combines construct pZC0508 (pX601 -meCMV-coDMD-N-R2R15-IMPDH) and construct pZC401. FIG. 16B shows the dystrophin expression in HEK293 cells transfected with these Dys-N and Dys-C constructs at the specified amounts of plasmids (μg).HEK293 cell lysate transfected with FL-dystrophin construct was used as a positive control(pXL780 1.0μg) and GAPDH was used as a loading control. The Densitometry quantification ofNFL-dystrophin expression is shown in FIG. 16C

[0224] Building upon the dual vector approach to assemble a near-full-length dystrophin, alternative constructs of NFL (N) were designed (FIG. 17A) - pZC521, pZC522, pZC530, and pZC531. Expression of each NFL(N) construct were evaluated with NFL(C) construct pZC400.(FIG. 17B and 17C).

[0225] MATERIALS AND METHODS

[0226] Plasmid construction

[0227] The plasmid expressing full-length (FL) dystrophin (p37-2iDMD-LR) was a gift fromMichele Calos (Addgene # 88892). The dystrophin fragments, Cfa, Gp41-1, and IMPDH- 1 inteins were amplified by fusion PCR, restriction digested and ligated into pAAV vectors harboring a mini-CMV promoter with a muscle creatine kinase enhancer (meCMV) and a mini-poly A signal.The plasmids were confirmed by Sanger sequencing and / or whole plasmid sequencing. Plasmid details are provided in the table below.

[0228] Table 2: Expression System Components

[0229] Cell culture and transfection[00230J AD293 cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM)(Corning, Manassas, VA) supplemented with 10% fetal bovine serum (FBS) and 1% lOOx penicillin-streptomycin solution (10,000 U / ml, Invitrogen). Cells were plated in 6-well plates and incubated overnight at 37°C. When the cultures reached 80% confluence, they were transfected with plasmids expressing full-length or dystrophin fragments using PEI (Polysciences Inc.,Pennsylvania, USA). At 72 hours after transfection, cells were collected for protein extraction.

[0231] AAV vector production, titer determination, and in vivo administration

[0232] The MyoAAV4A vectors were produced in suspension 293 cells by triple transfection and purified by OptiPrep lodixanol gradient ultracentrifugation in the lab or by the Viral VectorCore at Indiana University. Buffer exchange and concentration were carried out using the Amicon centrifugal filter units (MWCO 100 kDa). The final AAV particles were stored in PBS with0.001% Pluronic F-68 and 200 mM NaCl. All AAV vectors were titered using quantitative real- time PCR (qPCR). Briefly, the AAV particles were treated with Dnase I (Invitrogen, MA, USA)to eliminate any contaminating plasmid DNA, followed by proteinase K (New England Biolabs,MA, USA) digestion to release the transgene. Real-time PCR was performed using PowerUpSYBR Green Master Mix (Applied Biosystems, Thermo Fisher Scientific, MA, USA) in ABIQuantStudio 5 Real-Time PCR System (Applied Biosystems, Thermo Fisher Scientific, MA,USA). Samples were quantified by a standard curve established by serially diluted Smal -linearized plasmids. Titers are expressed as DNase resistant particles in vector genome per ml (vg / ml): 5.15 x 1013vg / ml for MyoAAV4A-Dys-Nl, 4.63 x 1013vg / ml for MyoAAV4A-Dys-M3, and 2 x 1013vg / ml for MyoAAV4A-Dys-C6. The AAV particles (a total of 2 x 1014 vg / kg, 2: 1 : 1 of Nl, M3 and C6) were systemically administered into a total of 13 mdx4cvmice at 3-4 weeks of age through retro-orbital injection as described previously by Xu et al, Nature Communications 2021; 12:3719.

[0233] Measurement of serum biomarkers

[0234] Blood samples were collected at various time points after retro-orbital injection. The blood samples were allowed to clot for 15 min to 30 min and centrifuged at 2300g for 10 min at room temperature. The supernatant was collected as serum and stored at -80 °C in small aliquots for the biochemical assays. Measurement of creatinine kinase (CK) (326-10, SEKISUI DiagnosticsLLC, serum alanine aminotransferase (ALT) (Abeam, ab 105134), serum aspartate aminotransferase (AST) (Abeam, ab 105135) were performed according to the manufacturer’s protocols.

[0235] Muscle contractility

[0236] At 8-12 weeks of age, muscle contractility was measured weekly using an in vivo muscle test system (Aurora Scientific Inc) as described previously by by Xu et al., Nature communications 2021;12:3719; Li et ah, Molecular Therapy : The Journal of the American Society of Gene Therapy 2023;31 :398-408; and Li et al., Nature Communications 2023; 14; 178. Mice wereanesthetized with 3% (w / v) isoflurane and anesthesia was maintained by 1.5% isoflurane (w / v) during muscle contractility measurement. Maximum plantarflexion tetanic torque was measured during a train of supramaximal electric stimulations of the tibial nerve (pulse frequency 150 Hz, pulse duration 0.2 ms) using the DMA v5.501 (Aurora Scientific Inc). The average torques for each mouse measured are shown in FIG. 7B.

[0237] Wire hanging assay

[0238] The animal was placed on a custom-made wire mesh, then inverted and suspended above a soft cushion. The latency to when the animal falls was recorded. The mouse was trained2-3 times one week before the test. This test is performed three days per week with 2-3 trials per session. The average performance for each session is presented as the average of the trials, and the average for three days is used as the average of the mouse.

[0239] Western blot

[0240] Cell pellets and mouse tissue samples were lysed using a cold radioimmunoprecipitation analysis buffer (RIP A) supplemented with lx protease inhibitor cocktail (ThermoScientific, 78440). Protein concentrations were measured to ensure uniform loading (Bio-Rad DC protein assay kit, 5000111). Proteins were separated using 4-15% precast SDS-PAGE gel Bio-Rad, 17000927) and transferred onto 0.45 μm nitrocellulose membranes (Bio-Rad, 1620115).After blocking with 5% non-fat dry milk, membranes were incubated with an anti-dystrophin antibody (Anti-N-terminus: MANHINGE1B(1OF9), 1: 1,00, Developmental Studies HybridomaBank, Iowa City, IA, USA; anti-M-fragment: MANEX50(6A9), 1 : 100, Developmental StudiesHybridoma Bank, Iowa City, IA, USA; anti-C -terminus: abl5277, 1 : 1000, Abeam, Cambridge,UK) or rabbit monoclonal anti-GAPDH antibody (Cell Signaling Technology, 2118S, 1 :2000).Subsequently, membranes were washed and incubated with Horseradish peroxide (HRP)-conjugated goat anti-mouse (7076 S, 1 :4000, Cell Signaling Technology) and goat anti-rabbit(7074 S, 1 :4000, Cell Signaling Technology) secondary antibodies. Chemiluminescent detection was employed using enhanced chemiluminescence (ECL) western blotting substrate (PierceBiotechnology, Rockford, IL, USA), capturing the signal by ChemiDoc XRS+ system (Bio-Rad).Western blots were quantified using Image! 1.54 software.

[0241] Histopathological and immunohistochemical assessment of tissues

[0242] Mouse tissues (heart, diaphragm and gastrocnemius) were harvested, embedded in optimal cutting temperature (OCT, Sakura Finetek, Netherlands) compound, snap-frozen in cold isopentane, and stored at -80°C. ForH&E staining, frozen cryosections (10 μm) of skeletal muscle and heart were fixed in 10% formaldehyde for 5 min at room temperature and then proceeded to the standard protocol of H&E staining. All images were taken under an Axio observer 7 Zeiss microscope (Carl Zeiss Microscopy, LLC, Thornwood, NY, USA). For Masson's trichrome staining, the muscle and heart cryosections were fixed with Bouin’s solution for 1 hour at 56 °C.After washing with PBS, the tissue sections were stained with Masson's 2000 Trichrome Kit(American MasterTech, Lodi, CA) following the manufacturer’s instruction. For immunohistological examinations, frozen cryosections (10 μm) were fixed with 4% paraformaldehyde for 15 minutes at room temperature. After washing with PBS, the slides were blocked with 3% BSA for 1 hour. The slides were incubated with primary antibodies against dystrophin as described herein and laminin-a2 (AEX-804-190-C100, 1 : 100, Enzo Life SciencesInc, Farmingdale, NY) , α-dystroglycan (IIH6 C4, 1 : 10, Developmental Studies Hybridoma Bank,Iowa City, IA, USA), β-dystroglycan (sc-33702, 1 :50, Santa Cruz Biotechnology, Dallas, TX,USA ), α-sarcoglycan (ab234589, 1: 100, Abeam, , Cambridge, UK), β-sarcoglycan (sc-14176,1 :50, Santa Cruz Biotechnology, Dallas, TX, USA), nNOS (sc-5302, 1 :50, Santa CruzBiotechnology, Dallas, TX, USA), and α-dystrobrevin (610766, 1 : 100, Becton Dickinson andCompany, NJ, USA) at room temperature for 0.5-1 hours. The slides were then washed extensively with PBS and incubated with secondary antibodies Alexa Fluor 488 goat anti -rat IgG (A- 11006,1 :400, Invitrogen, Carlsbad, CA) , Alexa Fluor 594 goat anti-mouse IgG (Al 1032, 1 :400,Invitrogen, Carlsbad, CA), Alexa Fluor Texas Red goat anti-rabbit IgG (T2767, 1 : 400, Invitrogen,Carlsbad, CA), or Alexa Fluor 568 goat anti-mouse IgM (A21043 1 :400, Invitrogen, Carlsbad,CA) for 1 hour at room temperature. The slides were sealed with VECTASHIELD AntifadeMounting Medium with DAPI (Vector Laboratory, Burlingame, CA). All images were taken under an Axio observer 7 Zeiss microscope (Carl Zeiss Microscopy, LLC, Thornwood, NY, USA) withZeiss ZEN version 3.8 (Carl Zeiss Microscopy, LLC, Thornwood, NY, USA). Laminin-α2- positive and dystrophin-positive muscle fibers, muscle fiber area, and fibrotic area were analyzed using the ImageJ 1.54f software. The amount of dystrophin positive muscle fibers is represented as a percentage of total laminin-α2-positive muscle fibers.

[0243] Statistical Analysis

[0244] The data were expressed as mean ± the standard error of the mean (SEM) and final figures were assembled with Adobe Photoshop 24.7.0. Statistical differences were determined by two-tailed unpaired Student’s t-test for two groups and one-way ANOVA with Tukey’s post tests for multiple group comparisons using GraphPad Prism 10.1.0 (Graphpad Software, La Jolla,California) with the assumption of Gaussian distribution of residuals. A p-value less than 0.05 was considered to be significant.EQUIVALENTS AND SCOPE

[0245] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of thepresent invention is not intended to be limited to the above, but rather is as set forth in the appended claims.

[0246] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0247] Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses and descriptive terms, from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.

[0248] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention is / are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity, those embodiments have not been specificallyset forth in haec verba herein. It is also noted that the term “comprising” is intended to be open and permits the inclusion of additional elements or steps.

[0249] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranged can assume any specific value or sub- range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0250] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of the ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art.Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5% or up to 1% of a given value. Alternatively, the term can mean within an order of magnitude, for example within 5-fold, or within 2 -fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0251] In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the method of the invention can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[0252] Sequence Listing

[0253] SEQ ID NO: 1 (Nucleotide sequence of full-length human dystrophin cDNA)

[0254] ATGCTTTGGTGGGAAGAAGTAGAGGACTGTTATGAAAGAGAAGATGTTCAAAAGAAAACATTCACAAAATGGGTAAATGCACAATTTTCTAAGTTTGGGAAGCAGCATATTGAGAACCTCTTCAGTGACCTACAGGATGGGAGGCGCCTCCTAGACCTCCTCGAAGGCCTGACAGGGCAAAAACTGCCAAAAGAAAAAGGATCCACAAGAGTTCATGCCCTGAACAATGTCAACAAGGCACTGCGGGTTTTGCAGAACAATAATGTTGATTTAGTGAATATTGGAAGTACTGACATCGTAGATGGAAATCATAAACTGACTCTTGGTTTGATTTGGAATATAATCCTCCACTGGCAGGTCAAAAATGTAATGAAAAATATCATGGCTGGATTGCAACAAACCAACAGTGAAAAGATTCTCCTGAGCTGGGTCCGACAATCAACTCGTAATTATCCACAGGTTAATGTAATCAACTTCACCACCAGCTGGTCTGATGGCCTGGCTTTGAATGCTCTCATCCATAGTCATAGGCCAGACCTATTTGACTGGAATAGTGTGGTTTGCCAGCAGTCAGCCACACAACGACTGGAACATGCATTCAACATCGCCAGATATCAATTAGGCATAGAGAAACTACTCGATCCTGAAGATGTTGATACCACCTATCCAGATAAGAAGTCCATCTTAATGTACATCACATCACTCTTCCAAGTTTTGCCTCAACAAGTGAGCATCGAAGCCATCCAGGAAGTGGAAATGTTGCCAAGGCCACCTAAAGTGACTAAAGAAGAACATTTTCAGTTACATCATCAAATGCACTATTCTCAACAGATCACGGTCAGTCTAGCACAGGGATATGAGAGAACTTCTTCCCCTAAGCCTCGATTCAAGAGCTATGCCTACACACAGGCTGCTTATGTCACCACCTCTGACCCTACACGGAGCCCATTTCCTTCACAGCATTTGGAAGCTCCTGAAGACAAGTCATTTGGCAGTTCATTGATGGAGAGTGAAGTAAACCTGGACCGTTATCAAACAGCTTTAGAAGAAGTATTATCGTGGCTTCTTTCTGCTGAGGACACATTGCAAGCACAAGGAGAGATTTCTAATGATGTGGAAGTGGTGAAAGACCAGTTTCATACTCATGAGGGGTACATGATGGATTTGACAGCCCATCAGGGCCGGGTTGGTAATATTCTACAATTGGGAAGTAAGCTGATTGGAACAGGAAAATTATCAGAAGATGAAGAAACTGAAGTACAAGAGCAGATGAATCTCCTAAATTCAAGATGGGAATGCCTCAGGGTAGCTAGCATGGAAAAACAAAGCAATTTACATAGAGTTTTAATGGATCTCCAGAATCAGAAACTGAAAGAGTTGAATGACTGGCTAACAAAAACAGAAGAAAGAACAAGGAAAATGGAGGAAGAGCCTCTTGGACCTGATCTTGAAGACCTAAAACGCCAAGTACAACAACATAAGGTGCTTCAAGAAGATCTAGAACAAGAACAAGTCAGGGTCAATTCTCTCACTCACATGGTGGTGGTAGTTGATGAATCTAGTGGAGATCACGCAACTGCTGCTTTGGAAGAACAACTTAAGGTATTGGGAGATCGATGGGCAAACATCTGTAGATGGACAGAAGACCGCTGGGTTCTTTTACAAGACATCCTTCTCAAATGGCAACGTCTTACTGAAGAACAGTGCCTTTTTAGTGCATGGCTTTCAGAAAAAGAAGATGCAGTGAACAAGATTCACACAACTGGCTTTAAAGATCAAAATGAAATGTTATCAAGTCTTCAAAAACTGGCCGTTTTAAAAGCGGATCTAGAAAAGAAAAAGCAATCCATGGGCAAACTGTATTCACTCAAACAAGATCTTCTTTCAACACTGAAGAATAAGTCAGTGACCCAGAAGACGGAAGCATGGCTGGATAACTTTGCCCGGTGTTGGGATAATTTAGTCCAAAAACTTGAAAAGAGTACAGCACAGATTTCACAGGCTGTCACCACCACTCAGCCATCACTAACACAGACAACTGTAATGGAAACAGTAACTACGGTGACCACAAGGGAACAGATCCTGGTAAAGCATGCTCAAGAGGAACTTCCACCACCACCTCCCCAAAAGAAGAGGCAGATTACTGTGGATTCTGAAATTAGGAAAAGGTTGGATGTTGATATAACTGAACTTCACAGCTGGATTACTCGCTCAGAAGCTGTGTTGCAGAGTCCTGAATTTGCAATCTTTCGGAAGGAAGGCAACTTCTCAGACTTAAAAGAAAAAGTCAATGCCATAGAGCGAGAAAAAGCTGAGAAGTTCAGAAAACTGCAAGATGCCAGCAGATCAGCTCAGGCCCTGGTGGAACAGATGGTGAATGAGGGTGTTAATGCAGATAGCATCAAACAAGCCTCAGAACAACTGAACAGCCGGTGGATCGAATTCTGCCAGTTGCTAAGTGAGAGACTTAACTGGCTGGAGTATCAGAACAACATCATCGCTTTCTATAATCAGCTACAACAATTGGAGCAGATGACAACTACTGCTGAAAACTGGTTGAAAATCCAACCCACCACCCCATCAGAGCCAACAGCAATTAAAAGTCAGTTAAAAATTTGTAAGGATGAAGTCAACCGGCTATCAGGTCTTCAACCTCAAATTGAACGATTAAAAATTCAAAGCATAGCCCTGAAAGAGAAAGGACAAGGACCCATGTTCCTGGATGCAGACTTTGTGGCCTTTACAAATCATTTTAAGCAAGTCTTTTCTGATGTGCAGGCCAGAGAGAAAGAGCTACAGACAATTTTTGACACTTTGCCACCAATGCGCTATCAGGAGACCATGAGTGCCATCAGGACATGGGTCCAGCAGTCAGAAACCAAACTCTCCATACCTCAACTTAGTGTCACCGACTATGAAATCATGGAGCAGAGACTCGGGGAATTGCAGGCTTTACAAAGTTCTCTGCAAGAGCAACAAAGTGGCCTATACTATCTCAGCACCACTGTGAAAGAGATGTCGAAGAAAGCGCCCTCTGAAATTAGCCGGAAATATCAATCAGAATTTGAAGAAATTGAGGGACGCTGGAAGAAGCTCTCCTCCCAGCTGGTTGAGCATTGTCAAAAGCTAGAGGAGCAAATGAATAAACTCCGAAAAATTCAGAATCACATACAAACCCTGAAGAAATGGATGGCTGAAGTTGATGTTTTTCTGAAGGAGGAATGGCCTGCCCTTGGGGATTCAGAAATTCTAAAAAAGCAGCTGAAACAGTGCAGACTTTTAGTCAGTGATATTCAGACAATTCAGCCCAGTCTAAACAGTGTCAATGAAGGTGGGCAGAAGATAAAGAATGAAGCAGAGCCAGAGTTTGCTTCGAGACTTGAGACAGAACTCAAAGAACTTAACACTCAGTGGGATCACATGTGCCAACAGGTCTATGCCAGAAAGGAGGCCTTGAAGGGAGGTTTGGAGAAAACTGTAAGCCTCCAGAAAGATCTATCAGAGATGCACGAATGGATGACACAAGCTGAAGAAGAGTATCTTGAGAGAGATTTTGAATATAAAACTCCAGATGAATTACAGAAAGCAGTTGAAGAGATGAAGAGAGCTAAAGAAGAGGCCCAACAAAAAGAAGCGAAAGTGAAACTCCTTACTGAGTCTGTAAATAGTGTCATAGCTCAAGCTCCACCTGTAGCACAAGAGGCCTTAAAAAAGGAACTTGAAACTCTAACCACCAACTACCAGTGGCTCTGCACTAGGCTGAATGGGAAATGCAAGACTTTGGAAGAAGTTTGGGCATGTTGGCATGAGTTATTGTCATACTTGGAGAAAGCAAACAAGTGGCTAAATGAAGTAGAATTTAAACTTAAAACCACTGAAAACATTCCTGGCGGAGCTGAGGAAATCTCTGAGGTGCTAGATTCACTTGAAAATTTGATGCGACATTCAGAGGATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGTCATGGATGAGCTAATCAATGAGGAACTTGAGACATTTAATTCTCGTTGGAGGGAACTACATGAAGAGGCTGTAAGGAGGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAAAATCCTTACACTTAATCCAGGAGTCCCTCACATTCATTGACAAGCAGTTGGCAGCTTATATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAAAATCCAATCTGATTTGACAAGTCATGAGATCAGTTTAGAAGAAATGAAGAAACATAATCAGGGGAAGGAGGCTGCCCAAAGAGTCCTGTCTCAGATTGATGTTGCACAGAAAAAATTACAAGATGTCTCCATGAAGTTTCGATTATTCCAGAAACCAGCCAATTTTGAGCAGCGTCTACAAGAAAGTAAGATGATTTTAGATGAAGTGAAGATGCACTTGCCTGCATTGGAAACAAAGAGTGTGGAACAGGAAGTAGTACAGTCACAGCTAAATCATTGTGTGAACTTGTATAAAAGTCTGAGTGAAGTGAAGTCTGAAGTGGAAATGGTGATAAAGACTGGACGTCAGATTGTACAGAAAAAGCAGACGGAAAATCCCAAAGAACTTGATGAAAGAGTAACAGCTTTGAAATTGCATTATAATGAGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTTGGAGAAATGCTTGAAATTGTCCCGTAAGATGCGAAAGGAAATGAATGTCTTGACAGAATGGCTGGCAGCTACAGATATGGAATTGACAAAGAGATCAGCAGTTGAAGGAATGCCTAGTAATTTGGATTCTGAAGTTGCCTGGGGAAAGGCTACTCAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACAGAGGTAGGAGAGGCCTTGAAAACAGTTTTGGGCAAGAAGGAGACGTTGGTGGAAGATAAACTCAGTCTTCTGAATAGTAATTGGATAGCTGTCACCTCCCGAGCAGAAGAGTGGTTAAATCTTTTGTTGGAATACCAGAAACACATGGAAACTTTTGACCAGAATGTGGACCACATCACAAAGTGGATCATTCAGGCTGACACACTTTTGGATGAATCAGAGAAAAAGAAACCCCAGCAAAAAGAAGACGTGCTTAAGCGTTTAAAGGCAGAACTGAATGACATACGCCCAAAGGTGGACTCTACACGTGACCAAGCAGCAAACTTGATGGCAAACCACGGTGACCACTGCAGGAAATTAGTAGAGCCCCAAATCTCAGAGCTCAACCATCGATTTGCAGCCATTTCACACAGAATTAAGACTGGAAAGGCCTCCATTCCTTTGAAGGAATTGGAGCAGTTTAACTCAGATATACAAAAATTGCTTGAACCACTGGAGGCTGAAATTCAGCAGGGGGTGAATCTGAAAGAGGAAGACTTCAATAAAGATATGAATGAAGACAATGAGGGTACTGTAAAAGAATTGTTGCAAAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGCGAGAGGAAATAAAGATAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGAAGAAAAAAGGCTCTAGAAATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGATCTCCTGAAATGCTTGGATGACATTGAAAAAAAATTAGCCAGCCTACCTGAGCCCAGAGATGAAAGGAAAATAAAGGAAATTGATCGGGAATTGCAGAAGAAGAAAGAGGAGCTGAATGCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCCAACTCAGATCCAGCTCAGCAAGCGCTGGCGGGAAATTGAGAGCAAATTTGCTCAGTTTCGAAGACTCAACTTTGCACAAATTCACACTGTCCGTGAAGAAACGATGATGGTGATGACTGAAGACATGCCTTTGGAAATTTCTTATGTGCCTTCTACTTATTTGACTGAAATCACTCATGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTAAGGACTTTGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTACAACAAAGCTCAGGTCGGATTGACATTATTCATAGCAAGAAGACAGCAGCATTGCAAAGTGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCCCAGCTTGATTTCCAATGGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAGAAATGGCGGCGTTTTCATTATGATATAAAGATATTTAATCAGTGGCTAACAGAAGCTGAACAGTTTCTCAGAAAGACACAAATTCCTGAGAATTGGGAACATGCTAAATACAAATGGTATCTTAAGGAACTCCAGGATGGCATTGGGCAGCGGCAAACTGTTGTCAGAACATTGAATGCAACTGGGGAAGAAATAATTCAGCAATCCTCAAAAACAGATGCCAGTATTCTACAGGAAAAATTGGGAAGCCTGAATCTGCGGTGGCAGGAGGTCTGCAAACAGCTGTCAGACAGAAAAAAGAGGCTAGAAGAACAAAAGAATATCTTGTCAGAATTTCAAAGAGATTTAAATGAATTTGTTTTATGGTTGGAGGAAGCAGATAACATTGCTAGTATCCCACTTGAACCTGGAAAAGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGAGTTGCCCCTGCGCCAGGGCCGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCTCCCATAAGCCCAGAAGAGCAAGATAAACTTGAAAATAAGCTCAAGCAGACAAATCTCCAGTGGATAAAGGTTTCCAGAGCTTTACCTGAGAAACAAGGAGAAATTGAAGCTCAAATAAAAGACCTTGGGCAGCTTGAAAAAAAGCTTGAAGACCTTGAAGAGCAGTTAAATCATCTGCTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGAAGGACCATTTGACGTTAAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGGAAGAGATTTTGTCTAAAGGGCAGCATTTGTACAAGGAAAAACCAGCCACTCAGCCAGTGAAGAGGAAGTTAGAAGATCTGAGCTCTGAGTGGAAGGCGGTAAACCGTTTACTTCAAGAGCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGAGCCTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAA

[0255] SEQ ID NO: 2 (Amino acid sequence of full-length human dystrophin protein)

[0256] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDE S SGDHAT AALEEQLKVLGDRW ANICRWTEDRWVLLQDILLKWQRLTEEQCLF S AWL SEKED AVNKIHTTGFKDQNEML S SLQKL AVLK ADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVD SEIRKRLD VDITELHS WITRSEA VLQ SPEF AIFRKEGNFSDLKEKVNAIEREKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKICKDEVNRL SGLQPQIERLKIQ SIALKEKGQGPMFLD ADF VAFTNHFKQ VF SD VQ AREKELQTIFDTLPPMRYQETMS AIRTWVQQ SETKL SIPQLS VTD YEIMEQRLGELQ ALQ S SLQEQQSGLYYLSTTVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKKWMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKDLSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVAQEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQ AEGL SEDGAAMA VEPTQIQL SKRWREIESKF AQFRRLNF AQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDE S SEWKAVNRLLQELRAKQPDLAPGLTTIGASPTQTVTLVTQP VVTKET AISKLEMP S SLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0257] SEQ ID NO: 3 (Nucleotide sequence of Dys-Nl)

[0258] ATGCTTTGGTGGGAAGAAGTAGAGGACTGTTATGAAAGAGAAGATGTTCAAAAGAAAACATTCACAAAATGGGTAAATGCACAATTTTCTAAGTTTGGGAAGCAGCATATTGAGAACCTCTTCAGTGACCTACAGGATGGGAGGCGCCTCCTAGACCTCCTCGAAGGCCTGACAGGGCAAAAACTGCCAAAAGAAAAAGGATCCACAAGAGTTCATGCCCTGAACAATGTCAACAAGGCACTGCGGGTTTTGCAGAACAATAATGTTGATTTAGTGAATATTGGAAGTACTGACATCGTAGATGGAAATCATAAACTGACTCTTGGTTTGATTTGGAATATAATCCTCCACTGGCAGGTCAAAAATGTAATGAAAAATATCATGGCTGGATTGCAACAAACCAACAGTGAAAAGATTCTCCTGAGCTGGGTCCGACAATCAACTCGTAATTATCCACAGGTTAATGTAATCAACTTCACCACCAGCTGGTCTGATGGCCTGGCTTTGAATGCTCTCATCCATAGTCATAGGCCAGACCTATTTGACTGGAATAGTGTGGTTTGCCAGCAGTCAGCCACACAACGACTGGAACATGCATTCAACATCGCCAGATATCAATTAGGCATAGAGAAACTACTCGATCCTGAAGATGTTGATACCACCTATCCAGATAAGAAGTCCATCTTAATGTACATCACATCACTCTTCCAAGTTTTGCCTCAACAAGTGAGCATCGAAGCCATCCAGGAAGTGGAAATGTTGCCAAGGCCACCTAAAGTGACTAAAGAAGAACATTTTCAGTTACATCATCAAATGCACTATTCTCAACAGATCACGGTCAGTCTAGCACAGGGATATGAGAGAACTTCTTCCCCTAAGCCTCGATTCAAGAGCTATGCCTACACACAGGCTGCTTATGTCACCACCTCTGACCCTACACGGAGCCCATTTCCTTCACAGCATTTGGAAGCTCCTGAAGACAAGTCATTTGGCAGTTCATTGATGGAGAGTGAAGTAAACCTGGACCGTTATCAAACAGCTTTAGAAGAAGTATTATCGTGGCTTCTTTCTGCTGAGGACACATTGCAAGCACAAGGAGAGATTTCTAATGATGTGGAAGTGGTGAAAGACCAGTTTCATACTCATGAGGGGTACATGATGGATTTGACAGCCCATCAGGGCCGGGTTGGTAATATTCTACAATTGGGAAGTAAGCTGATTGGAACAGGAAAATTATCAGAAGATGAAGAAACTGAAGTACAAGAGCAGATGAATCTCCTAAATTCAAGATGGGAATGCCTCAGGGTAGCTAGCATGGAAAAACAAAGCAATTTACATAGAGTTTTAATGGATCTCCAGAATCAGAAACTGAAAGAGTTGAATGACTGGCTAACAAAAACAGAAGAAAGAACAAGGAAAATGGAGGAAGAGCCTCTTGGACCTGATCTTGAAGACCTAAAACGCCAAGTACAACAACATAAGGTGCTTCAAGAAGATCTAGAACAAGAACAAGTCAGGGTCAATTCTCTCACTCACATGGTGGTGGTAGTTGATGAATCTAGTGGAGATCACGCAACTGCTGCTTTGGAAGAACAACTTAAGGTATTGGGAGATCGATGGGCAAACATCTGTAGATGGACAGAAGACCGCTGGGTTCTTTTACAAGACATCCTTCTCAAATGGCAACGTCTTACTGAAGAACAGTGCCTTTTTAGTGCATGGCTTTCAGAAAAAGAAGATGCAGTGAACAAGATTCACACAACTGGCTTTAAAGATCAAAATGAAATGTTATCAAGTCTTCAAAAACTGGCCGTTTTAAAAGCGGATCTAGAAAAGAAAAAGCAATCCATGGGCAAACTGTATTCACTCAAACAAGATCTTCTTTCAACACTGAAGAATAAGTCAGTGACCCAGAAGACGGAAGCATGGCTGGATAACTTTGCCCGGTGTTGGGATAATTTAGTCCAAAAACTTGAAAAGAGTACAGCACAGATTTCACAGGCTGTCACCACCACTCAGCCATCACTAACACAGACAACTGTAATGGAAACAGTAACTACGGTGACCACAAGGGAACAGATCCTGGTAAAGCATGCTCAAGAGGAACTTCCACCACCACCTCCCCAAAAGAAGAGGCAGATTACTGTGGATTCTGAAATTAGGAAAAGGTTGGATGTTGATATAACTGAACTTCACAGCTGGATTACTCGCTCAGAAGCTGTGTTGCAGAGTCCTGAATTTGCAATCTTTCGGAAGGAAGGCAACTTCTCAGACTTAAAAGAAAAAGTCAATGCCATAGAGCGAGAAAAAGCTGAGAAGTTCAGAAAACTGCAAGATGCCAGCAGATCAGCTCAGGCCCTGGTGGAACAGATGGTGAATGAGGGTGTTAATGCAGATAGCATCAAACAAGCCTCAGAACAACTGAACAGCCGGTGGATCGAATTCTGCCAGTTGCTAAGTGAGAGACTTAACTGGCTGGAGTATCAGAACAACATCATCGCTTTCTATAATCAGCTACAACAATTGGAGCAGATGACAACTACTGCTGAAAACTGGTTGAAAATCCAACCCACCACCCCATCAGAGCCAACAGCAATTAAAAGTCAGTTAAAAATTTGTAAGGATGAAGTCAACCGGCTATCAGGTCTTCAACCTCAAATTGAACGATTAAAAATTCAAAGCATAGCCCTGAAAGAGAAAGGACAAGGACCCATGTTCCTGGATGCAGACTTTGTGGCCTTTACAAATCATTTTAAGCAAGTCTTTTCTGATGTGCAGGCCAGAGAGAAAGAGCTACAGACAATTTTTGACACTTTGCCACCAATGCGCTATCAGGAGACCATGAGTGCCATCAGGACATGGGTCCAGCAGTCAGAAACCAAACTCTCCATACCTCAACTTAGTGTCACCGACTATGAAATCATGGAGCAGAGACTCGGGGAATTGCAGGCTTTACAAAGTTCTCTGCAAGAGCAACAAAGTGGCCTATACTATCTCAGCACCACTGTGAAAGAGATGTCGAAGAAAGCGCCCTCTGAAATTAGCCGGAAATATCAATCAGAATTTGAAGAAATTGAGGGACGCTGGAAGAAGCTCTCCTCCCAGCTGGTTGAGCATTGTCAAAAGCTAGAGGAGCAAATGAATAAACTCCGAAAAATTCAGAATCACATACAAACCCTGAAGAAATGGATGGCTGAAGTTGATGTTTTTCTGAAGGAGGAATGGCCTGCCCTTGGGGATTCAGAAATTCTAAAAAAGCAGCTGAAACAGTGCAGACTTTTAGTCAGTGATATTCAGACAATTCAGCCCAGTCTAAACAGTGTCAATGAAGGTGGGCAGAAGATAAAGAATGAAGCAGAGCCAGAGTTTGCTTCGAGACTTGAGACAGAACTCAAAGAACTTAACACTCAGTGGGATCACATGTGCCAACAGGTCTATGCCAGAAAGGAGGCCTTGAAGGGAGGTTTGGAGAAAACTGTAAGCCTCCAGAAAGATCTATCAGAGATGCACGAATGGATGACACAAGCTGAAGAAGAGTATCTTGAGAGAGATTTTGAATATAAAACTCCAGATGAATTACAGAAAGCAGTTGAAGAGATGAAGAGAGCTAAAGAAGAGGCCCAACAAAAAGAAGCGAAAGTGAAACTCCTTACTGAGTCTGTAAATAGTGTCATAGCTCAAGCTCCACCTGTAGCACAAGAGGCCTTAAAAAAGGAACTTGAAACTCTAACCACCAACTACCAGTGGCTCTGCACTAGGCTGAATGGGAAATGCAAGACTTTGGAAGAAGTTTGGGCATGTCTCAGTTATGACACCGAAATCCTGACAGTCGAGTATGGATTTCTGCCGATCGGCAAGATTGTGGAGGAGAGAATTGAATGTACGGTCTATACGGTCGACAAGAATGGTTTCGTCTACACCCAACCAATTGCTCAATGGCATAATCGAGGGGAGCAGGAGGTGTTTGAGTATTGCCTGGAGGACGGGTCAATCATTAGAGCTACAAAGGACCATAAGTTTATGACAACCGATGGTCAAATGCTGCCGATAGATGAAATATTCGAAAGGGGACTGGATCTTAAGCAAGTCGATGGCCTTCCA

[0259] SEQ ID NO: 4 (Amino acid sequence of Dys-Nl)

[0260] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDE S SGDHAT AALEEQLKVLGDRW ANICRWTEDRWVLLQDILLKWQRLTEEQCLF S AWL SEKED AVNKIHTTGFKDQNEML S SLQKL AVLK ADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVD SEIRKRLD VDITELHS WITRSEA VLQ SPEF AIFRKEGNFSDLKEKVNAIEREKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKICKDEVNRL SGLQPQIERLKIQ SIALKEKGQGPMFLD ADF VAFTNHFKQ VF SD VQ AREKELQTIFDTLPPMRYQETMS AIRTWVQQ SETKL SIPQLS VTD YEIMEQRLGELQ ALQ S SLQEQQSGLYYLSTTVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKKWMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKDLSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVAQEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGFVYTQPIAQWHNRGEQEVFEYCLEDGSIIRATKDHKFMTTDGQMLPIDEIFERGLDLKQVDGLP

[0261] SEQ ID NO: 5 (Nucleotide sequence of Dys-Ml)

[0262] ATGGTCAAGATTATCAGCCGCAAATCCTTGGGGACACAGAATGTATATGACATCGGCGTGGAAAAGGATCACAATTTTCTGCTGAAGAATGGTCTTGTTGCTTCCAATTGTTGGCATGAGTTATTGTCATACTTGGAGAAAGCAAACAAGTGGCTAAATGAAGTAGAATTTAAACTTAAAACCACTGAAAACATTCCTGGCGGAGCTGAGGAAATCTCTGAGGTGCTAGATTCACTTGAAAATTTGATGCGACATTCAGAGGATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGTCATGGATGAGCTAATCAATGAGGAACTTGAGACATTTAATTCTCGTTGGAGGGAACTACATGAAGAGGCTGTAAGGAGGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAAAATCCTTACACTTAATCCAGGAGTCCCTCACATTCATTGACAAGCAGTTGGCAGCTTATATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAAAATCCAATCTGATTTGACAAGTCATGAGATCAGTTTAGAAGAAATGAAGAAACATAATCAGGGGAAGGAGGCTGCCCAAAGAGTCCTGTCTCAGATTGATGTTGCACAGAAAAAATTACAAGATGTCTCCATGAAGTTTCGATTATTCCAGAAACCAGCCAATTTTGAGCAGCGTCTACAAGAAAGTAAGATGATTTTAGATGAAGTGAAGATGCACTTGCCTGCATTGGAAACAAAGAGTGTGGAACAGGAAGTAGTACAGTCACAGCTAAATCATTGTGTGAACTTGTATAAAAGTCTGAGTGAAGTGAAGTCTGAAGTGGAAATGGTGATAAAGACTGGACGTCAGATTGTACAGAAAAAGCAGACGGAAAATCCCAAAGAACTTGATGAAAGAGTAACAGCTTTGAAATTGCATTATAATGAGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTTGGAGAAATGCTTGAAATTGTCCCGTAAGATGCGAAAGGAAATGAATGTCTTGACAGAATGGCTGGCAGCTACAGATATGGAATTGACAAAGAGATCAGCAGTTGAAGGAATGCCTAGTAATTTGGATTCTGAAGTTGCCTGGGGAAAGGCTACTCAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACAGAGGTAGGAGAGGCCTTGAAAACAGTTTTGGGCAAGAAGGAGACGTTGGTGGAAGATAAACTCAGTCTTCTGAATAGTAATTGGATAGCTGTCACCTCCCGAGCAGAAGAGTGGTTAAATCTTTTGTTGGAATACCAGAAACACATGGAAACTTTTGACCAGAATGTGGACCACATCACAAAGTGGATCATTCAGGCTGACACACTTTTGGATGAATCAGAGAAAAAGAAACCCCAGCAAAAAGAAGACGTGCTTAAGCGTTTAAAGGCAGAACTGAATGACATACGCCCAAAGGTGGACTCTACACGTGACCAAGCAGCAAACTTGATGGCAAACCACGGTGACCACTGCAGGAAATTAGTAGAGCCCCAAATCTCAGAGCTCAACCATCGATTTGCAGCCATTTCACACAGAATTAAGACTGGAAAGGCCTCCATTCCTTTGAAGGAATTGGAGCAGTTTAACTCAGATATACAAAAATTGCTTGAACCACTGGAGGCTGAAATTCAGCAGGGGGTGAATCTGAAAGAGGAAGACTTCAATAAAGATATGAATGAAGACAATGAGGGTACTGTAAAAGAATTGTTGCAAAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGCGAGAGGAAATAAAGATAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGAAGAAAAAAGGCTCTAGAAATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGATCTCCTGAAATGCTTGGATGACATTGAAAAAAAATTAGCCAGCCTACCTGAGCCCAGAGATGAAAGGAAAATAAAGGAAATTGATCGGGAATTGCAGAAGAAGAAAGAGGAGCTGAATGCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCCAACTCAGATCCAGCTCAGCAAGCGCTGGCGGGAAATTGAGAGCAAATTTGCTCAGTTTCGAAGACTCAACTTTGCACAAATTCACACTGTCCGTGAAGAAACGATGATGGTGATGACTGAAGACATGCCTTTGGAAATTTCTTATGTGCCTTCTACTTATTTGACTGAAATCACTCATGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTAAGGACTTTGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTACAACAAAGCTCAGGTCGGATTGACATTATTCATAGCAAGAAGACAGCAGCATTGCAAAGTGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCCCAGCTTGATTTCCAATGGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAGAAATGGCGGCGTTTTCATTATGATATAAAGATATTTAATCAGTGGCTAACAGAAGCTGAACAGTTTCTCAGAAAGACACAAATTCCTGAGAATTGGGAACATGCTAAATACAAATGGTATCTTAAGGAACTCCAGGATGGCATTGGGCAGCGGCAAACTGTTGTCAGAACATTGAATGCAACTGGGGAAGAAATAATTCAGCAATCCTCAAAAACAGATGCCAGTATTCTACAGGAAAAATTGGGAAGCCTGAATCTGCGGTGGCAGGAGGTCTGCAAACAGCTGTCAGACAGAAAAAAGAGGCTAGAAGAACAAAAGAATATCTTGTCAGAATTTCAAAGAGATTTAAATGAATTTGTTTTATGGTTGGAGGAAGCAGATAACATTGCTAGTATCCCACTTGAACCTGGAAAAGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGAGTTGCCCCTGCGCCAGGGCCGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCTCCCATAAGCCCAGAAGAGCAAGATAAACTTGAAAATAAGCTCAAGCAGACAAATCTCCAGTGGATAAAGGTTTCCAGAGCTTTACCTGAGAAACAAGGAGAAATTGAAGCTCAAATAAAAGACCTTGGGCAGCTTGAAAAAAAGCTTGAAGACCTTGAAGAGCAGTTAAATCATCTGCTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGAAGGACCATTTGACGTTAAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGGAAGAGATTTTGTCTAAAGGGCAGCATTTGTACAAGGAAAAACCAGCCACTCAGCCAGTGAAGAGGAAGTTAGAAGATCTGAGCTCTGAGTGGAAGGCGGTAAACCGTTTACTTCAAGAGCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGAGCCTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGAA

[0263] SEQ ID NO: 6 (Amino acid sequence of Dys-Ml)

[0264] MVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGASPTQTVTLVTQPVVTKETAISKLEMPCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0265] SEQ ID NO: 7 (Nucleotide sequence of Dys-Cl)

[0266] ATGATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGgtaagtagagggctgggctgggctgtggggggtgt ggggtgcgggactgggcagtctgggagtccctctcaccacttttcttacctttctagGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0267] SEQ ID NO: 8 (Amino acid sequence of Dys-Cl)

[0268] MMLKKILKIEELDERELIDIEVSGNHLFYANDILTHNSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQESHDDTHSRFEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFP S SRGRNTPGKPMREDTM

[0269] SEQ ID NO: 9 (Nucleotide sequence of Dys-M2)

[0270] ATGGTCAAGATTATCAGCCGCAAATCCTTGGGGACACAGAATGTATATGACATCGGCGTGGAAAAGGATCACAATTTTCTGCTGAAGAATGGTCTTGTTGCTTCCAATTGTTGGCATGAGTTATTGTCATACTTGGAGAAAGCAAACAAGTGGCTAAATGAAGTAGAATTTAAACTTAAAACCACTGAAAACATTCCTGGCGGAGCTGAGGAAATCTCTGAGGTGCTAGATTCACTTGAAAATTTGATGCGACATTCAGAGGATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGTCATGGATGAGCTAATCAATGAGGAACTTGAGACATTTAATTCTCGTTGGAGGGAACTACATGAAGAGGCTGTAAGGAGGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAAAATCCTTACACTTAATCCAGGAGTCCCTCACATTCATTGACAAGCAGTTGGCAGCTTATATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAAAATCCAATCTGATTTGACAAGTCATGAGATCAGTTTAGAAGAAATGAAGAAACATAATCAGGGGAAGGAGGCTGCCCAAAGAGTCCTGTCTCAGATTGATGTTGCACAGAAAAAATTACAAGATGTCTCCATGAAGTTTCGATTATTCCAGAAACCAGCCAATTTTGAGCAGCGTCTACAAGAAAGTAAGATGATTTTAGATGAAGTGAAGATGCACTTGCCTGCATTGGAAACAAAGAGTGTGGAACAGGAAGTAGTACAGTCACAGCTAAATCATTGTGTGAACTTGTATAAAAGTCTGAGTGAAGTGAAGTCTGAAGTGGAAATGGTGATAAAGACTGGACGTCAGATTGTACAGAAAAAGCAGACGGAAAATCCCAAAGAACTTGATGAAAGAGTAACAGCTTTGAAATTGCATTATAATGAGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTTGGAGAAATGCTTGAAATTGTCCCGTAAGATGCGAAAGGAAATGAATGTCTTGACAGAATGGCTGGCAGCTACAGATATGGAATTGACAAAGAGATCAGCAGTTGAAGGAATGCCTAGTAATTTGGATTCTGAAGTTGCCTGGGGAAAGGCTACTCAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACAGAGGTAGGAGAGGCCTTGAAAACAGTTTTGGGCAAGAAGGAGACGTTGGTGGAAGATAAACTCAGTCTTCTGAATAGTAATTGGATAGCTGTCACCTCCCGAGCAGAAGAGTGGTTAAATCTTTTGTTGGAATACCAGAAACACATGGAAACTTTTGACCAGAATGTGGACCACATCACAAAGTGGATCATTCAGGCTGACACACTTTTGGATGAATCAGAGAAAAAGAAACCCCAGCAAAAAGAAGACGTGCTTAAGCGTTTAAAGGCAGAACTGAATGACATACGCCCAAAGGTGGACTCTACACGTGACCAAGCAGCAAACTTGATGGCAAACCACGGTGACCACTGCAGGAAATTAGTAGAGCCCCAAATCTCAGAGCTCAACCATCGATTTGCAGCCATTTCACACAGAATTAAGACTGGAAAGGCCTCCATTCCTTTGAAGGAATTGGAGCAGTTTAACTCAGATATACAAAAATTGCTTGAACCACTGGAGGCTGAAATTCAGCAGGGGGTGAATCTGAAAGAGGAAGACTTCAATAAAGATATGAATGAAGACAATGAGGGTACTGTAAAAGAATTGTTGCAAAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGCGAGAGGAAATAAAGATAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGAAGAAAAAAGGCTCTAGAAATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGATCTCCTGAAATGCTTGGATGACATTGAAAAAAAATTAGCCAGCCTACCTGAGCCCAGAGATGAAAGGAAAATAAAGGAAATTGATCGGGAATTGCAGAAGAAGAAAGAGGAGCTGAATGCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCCAACTCAGATCCAGCTCAGCAAGCGCTGGCGGGAAATTGAGAGCAAATTTGCTCAGTTTCGAAGACTCAACTTTGCACAAATTCACACTGTCCGTGAAGAAACGATGATGGTGATGACTGAAGACATGCCTTTGGAAATTTCTTATGTGCCTTCTACTTATTTGACTGAAATCACTCATGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTAAGGACTTTGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTACAACAAAGCTCAGGTCGGATTGACATTATTCATAGCAAGAAGACAGCAGCATTGCAAAGTGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCCCAGCTTGATTTCCAATGGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAGAAATGGCGGCGTTTTCATTATGATATAAAGATATTTAATCAGTGGCTAACAGAAGCTGAACAGTTTCTCAGAAAGACACAAATTCCTGAGAATTGGGAACATGCTAAATACAAATGGTATCTTAAGGAACTCCAGGATGGCATTGGGCAGCGGCAAACTGTTGTCAGAACATTGAATGCAACTGGGGAAGAAATAATTCAGCAATCCTCAAAAACAGATGCCAGTATTCTACAGGAAAAATTGGGAAGCCTGAATCTGCGGTGGCAGGAGGTCTGCAAACAGCTGTCAGACAGAAAAAAGAGGCTAGAAGAACAAAAGAATATCTTGTCAGAATTTCAAAGAGATTTAAATGAATTTGTTTTATGGTTGGAGGAAGCAGATAACATTGCTAGTATCCCACTTGAACCTGGAAAAGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGAGTTGCCCCTGCGCCAGGGCCGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCTCCCATAAGCCCAGAAGAGCAAGATAAACTTGAAAATAAGCTCAAGCAGACAAATCTCCAGTGGATAAAGGTTTCCAGAGCTTTACCTGAGAAACAAGGAGAAATTGAAGCTCAAATAAAAGACCTTGGGCAGCTTGAAAAAAAGCTTGAAGACCTTGAAGAGCAGTTAAATCATCTGCTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGAAGGACCATTTGACGTTAAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGGAAGAGATTTTGTCTAAAGGGCAGCATTTGTACAAGGAAAAACCAGCCACTCAGCCAGTGAAGAGGAAGTTAGAAGATCTGAGCTCTGAGTGGAAGGCGGTAAACCGTTTACTTCAAGAGCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGATACTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGAA

[0271] SEQ ID NO: 10 (Amino acid sequence of Dys-M2)

[0272] MVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQ ADTLLDE SEKKKPQQKED VLKRLKAELNDIRPKVD STRDQ AANLM ANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQFtLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0273] SEQ ID NO: 11 (Nucleotide sequence of Dys-C2)

[0274] ATGATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGG gtaagtagagggctgggctgggctgtggggggtgtggggtgcgggactgggcagtctgggagtccctctcaccacttttcttacctttctagGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0275] SEQ ID NO: 12 (Amino acid sequence of Dys-C2)

[0276] MMLKKILKIEELDERELIDIEVSGNHLFYANDILTHNSPTQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVD VANDEALKEERDYS ADD TRKVHMI FENINAS WRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRF S A YRT AMKLRRLQKALCLDLL SL S AACD ALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0277] SEQ ID NO: 13 (Nucleotide sequence of Dys-C3)

[0278] ATGATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0279] SEQ ID NO: 14 (Amino acid sequence of Dys-C3)

[0280] MMLKKILKIEELDERELIDIEVSGNHLFYANDILTHNSPTQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRF S AYR! AMKLRRLQKALCLDLL SL SAACD ALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0281] SEQ ID NO: 15 (Nucleotide sequence of Dys-C4)

[0282] ATGATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTTCTTCTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0283] SEQ ID NO: 16 (Amino acid sequence of Dys-C4)

[0284] MMLKKILKIEELDERELIDIEVSGNHLF YANDILTHNS S SQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRF S A YRT AMKLRRLQKALCLDLL SL S AACD ALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMG YEP VQTVLEGDNMETP VTLINFWP VD S AP AS SPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0285] SEQ ID NO: 17 (Nucleotide sequence of Dys-C5)

[0286] ATGCACAGCTGGAACTTCAAGCTGTACGTCATGATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTTCTTCTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0287] SEQ ID NO: 18 (Amino acid sequence of Dys-C5)

[0288] MHSWNFKLYVMMLKKILKIEELDERELIDIEVSGNHLF YANDILTHNS S SQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLID SLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQL SP YNL STLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERIL ADLEEENRNLQ AE YDRLKQQHEHKGL SPLPSPPEMMPT SPQ SPRD AELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSD S SQPMLLRVVGSQTSD SMGEEDLL SPPQDT STGLEEVMEQLNNSFP S SRGRNTPGKPMREDTM

[0289] SEQ ID NO: 19 (Nucleotide sequence of Dys-M3)

[0290] ATGGTCAAGATTATCAGCCGCAAATCCTTGGGGACACAGAATGTATATGACATCGGCGTGGAAAAGGATCACAATTTTCTGCTGAAGAATGGTCTTGTTGCTTCCAATTGTTGGCATGAGTTATTGTCATACTTGGAGAAAGCAAACAAGTGGCTAAATGAAGTAGAATTTAAACTTAAAACCACTGAAAACATTCCTGGCGGAGCTGAGGAAATCTCTGAGGTGCTAGATTCACTTGAAAATTTGATGCGACATTCAGAGGATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGTCATGGATGAGCTAATCAATGAGGAACTTGAGACATTTAATTCTCGTTGGAGGGAACTACATGAAGAGGCTGTAAGGAGGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAAAATCCTTACACTTAATCCAGGAGTCCCTCACATTCATTGACAAGCAGTTGGCAGCTTATATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAAAATCCAATCTGATTTGACAAGTCATGAGATCAGTTTAGAAGAAATGAAGAAACATAATCAGGGGAAGGAGGCTGCCCAAAGAGTCCTGTCTCAGATTGATGTTGCACAGAAAAAATTACAAGATGTCTCCATGAAGTTTCGATTATTCCAGAAACCAGCCAATTTTGAGCAGCGTCTACAAGAAAGTAAGATGATTTTAGATGAAGTGAAGATGCACTTGCCTGCATTGGAAACAAAGAGTGTGGAACAGGAAGTAGTACAGTCACAGCTAAATCATTGTGTGAACTTGTATAAAAGTCTGAGTGAAGTGAAGTCTGAAGTGGAAATGGTGATAAAGACTGGACGTCAGATTGTACAGAAAAAGCAGACGGAAAATCCCAAAGAACTTGATGAAAGAGTAACAGCTTTGAAATTGCATTATAATGAGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTTGGAGAAATGCTTGAAATTGTCCCGTAAGATGCGAAAGGAAATGAATGTCTTGACAGAATGGCTGGCAGCTACAGATATGGAATTGACAAAGAGATCAGCAGTTGAAGGAATGCCTAGTAATTTGGATTCTGAAGTTGCCTGGGGAAAGGCTACTCAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACAGAGGTAGGAGAGGCCTTGAAAACAGTTTTGGGCAAGAAGGAGACGTTGGTGGAAGATAAACTCAGTCTTCTGAATAGTAATTGGATAGCTGTCACCTCCCGAGCAGAAGAGTGGTTAAATCTTTTGTTGGAATACCAGAAACACATGGAAACTTTTGACCAGAATGTGGACCACATCACAAAGTGGATCATTCAGGCTGACACACTTTTGGATGAATCAGAGAAAAAGAAACCCCAGCAAAAAGAAGACGTGCTTAAGCGTTTAAAGGCAGAACTGAATGACATACGCCCAAAGGTGGACTCTACACGTGACCAAGCAGCAAACTTGATGGCAAACCACGGTGACCACTGCAGGAAATTAGTAGAGCCCCAAATCTCAGAGCTCAACCATCGATTTGCAGCCATTTCACACAGAATTAAGACTGGAAAGGCCTCCATTCCTTTGAAGGAATTGGAGCAGTTTAACTCAGATATACAAAAATTGCTTGAACCACTGGAGGCTGAAATTCAGCAGGGGGTGAATCTGAAAGAGGAAGACTTCAATAAAGATATGAATGAAGACAATGAGGGTACTGTAAAAGAATTGTTGCAAAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGCGAGAGGAAATAAAGATAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGAAGAAAAAAGGCTCTAGAAATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGATCTCCTGAAATGCTTGGATGACATTGAAAAAAAATTAGCCAGCCTACCTGAGCCCAGAGATGAAAGGAAAATAAAGGAAATTGATCGGGAATTGCAGAAGAAGAAAGAGGAGCTGAATGCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCCAACTCAGATCCAGCTCAGCAAGCGCTGGCGGGAAATTGAGAGCAAATTTGCTCAGTTTCGAAGACTCAACTTTGCACAAATTCACACTGTCCGTGAAGAAACGATGATGGTGATGACTGAAGACATGCCTTTGGAAATTTCTTATGTGCCTTCTACTTATTTGACTGAAATCACTCATGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTAAGGACTTTGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTACAACAAAGCTCAGGTCGGATTGACATTATTCATAGCAAGAAGACAGCAGCATTGCAAAGTGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCCCAGCTTGATTTCCAATGGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAGAAATGGCGGCGTTTTCATTATGATATAAAGATATTTAATCAGTGGCTAACAGAAGCTGAACAGTTTCTCAGAAAGACACAAATTCCTGAGAATTGGGAACATGCTAAATACAAATGGTATCTTAAGGAACTCCAGGATGGCATTGGGCAGCGGCAAACTGTTGTCAGAACATTGAATGCAACTGGGGAAGAAATAATTCAGCAATCCTCAAAAACAGATGCCAGTATTCTACAGGAAAAATTGGGAAGCCTGAATCTGCGGTGGCAGGAGGTCTGCAAACAGCTGTCAGACAGAAAAAAGAGGCTAGAAGAACAAAAGAATATCTTGTCAGAATTTCAAAGAGATTTAAATGAATTTGTTTTATGGTTGGAGGAAGCAGATAACATTGCTAGTATCCCACTTGAACCTGGAAAAGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGAGTTGCCCCTGCGCCAGGGCCGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCTCCCATAAGCCCAGAAGAGCAAGATAAACTTGAAAATAAGCTCAAGCAGACAAATCTCCAGTGGATAAAGGTTTCCAGAGCTTTACCTGAGAAACAAGGAGAAATTGAAGCTCAAATAAAAGACCTTGGGCAGCTTGAAAAAAAGCTTGAAGACCTTGAAGAGCAGTTAAATCATCTGCTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGAAGGACCATTTGACGTTAAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGGAAGAGATTTTGTCTAAAGGGCAGCATTTGTACAAGGAAAAACCAGCCACTCAGCCAGTGAAGAGGAAGTTAGAAGATCTGAGCTCTGAGTGGAAGGCGGTAAACCGTTTACTTCAAGAGCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGAGGCTGTTTTGTTCCGGGTACACTGGTGAATACCGAAAATGGTCTGAAAAAAATCGAAGAAATCAAAGTGGGCGACAAAGTGTTTAGCCATACCGGTAAACTGCAAGAAGTTGTTGATACCCTGATCTTTGATCGTGATGAAGAGATTATTAGCATCAACGGTATCGACTGCACCAAAAACCATGAGTTTTATGTGATCGACAAAGAAAATGCCAATCGCGTGAACGAAGATAACATTCACCTGTTTGCACGTTGGGTTCATGCCGAAGAACTGGATATGAAAAAACATCTGCTGATCGAGCTGGAA

[0291] SEQ ID NO: 20 (Amino acid sequence of Dys-M3)

[0292] MVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGACFVPGTLVNTENGLKKIEEIKVGDKVFSHTGKLQEVVDTLIFDRDEEIISINGIDCTKNHEFYVIDKENANRVNEDNIHLFARWVHAEELDMKKHLLIELE

[0293] SEQ ID NO: 21 (Nucleotide sequence of Dys-C6)

[0294] ATGCACAGCTGGAACTTCAAGCTGTACGTCATGAAATTCAAACTGAAAGAGATCACCAGCATCGAAACCAAACACTATAAAGGCAAAGTTCATGATCTGACCGTGAATCAGGATCATAGCTATAACGTTCGTGGCACCGTTGTTCATAACTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATG

[0295] SEQ ID NO: 22 (Amino acid sequence of Dys-C6)

[0296] MHSWNFKLYVMKFKLKEITSIETKHYKGKVHDLTVNQDHSYNVRGTVVHNSPTQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNFRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTEL YQ SL ADLNNVRF S A YRT AMKLRRLQKALCLDLLSL S AACD ALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISEE SEERGELERILADLEEENRNLQ AEYDRLKQQHEHKGLSPLP SPPEMMPT SPQ SPRD AELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPST SLQRSD S SQPMLLRVVGSQT SD SMGEEDLL SPPQDT STGLEEVMEQLNNSFPS SRGRNTPGKPMREDTM

[0297] SEQ ID NO: 23 (Mini-polyA signal)

[0298] AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0299] SEQ ID NO: 24 (Mini-CMV promoter)

[0300] GCATGCCCACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCC

[0301] SEQ ID NO: 25 (Muscle creatine kinase enhancer)

[0302] GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGG

[0303] SEQ ID NO: 26 (Spc5-12 promoter)

[0304] GGCCGTCCGCCTTCGGCACCATCCTCACGACACCCAAATATGGCGACGGGTGAGGAATGGTGGGGAGTTATTTTTAGAGCGGTGAGGAAGGTGGGCAGGCAGCAGGTGTTGGCGCTCTAAAAATAACTCCCGGGAGTTATTTTTAGAGCGGAGGAATGGTGGACACCCAAATATGGCGACGGTTCCTCACCCGTCGCCATATTTGGGTGTCCGCCCTCGGCCGGGGCCGCATTCCTGGGGGCCGGGCGGTGCTCCCGCCCGCCTCGATAAAAGGCTCCGGGGCCGGCGGCGGCCCACGAGCTACCCGGAGGAGCGGGAG

[0305] SEQ ID NO: 27 (Spc2-26 promoter)

[0306] GGCCGTCGCCATATTTGGGTGTCCCAACACCTGCTGCCTGCCCCGTCGCCATATTTGGGTGTCGGGAGTTATTTTTAGAGCGGACACCCAAATATGGCGACGGCCGGGGCCGCATTCCTGGGGGCCGGGCGGTGCTCCCGCCCGCCTCGATAAAAGGCTCCGGGGCCGGCGGCGGCCCACGA

[0307] SEQ ID NO: 28 (Strong Kozak sequence)

[0308] GCCACCATG

[0309] SEQ ID NO: 29 (Weak Kozak sequence)

[0310] CAGTTGATG

[0311] SEQ ID NO: 30 (PB29)

[0312] MHSWNFKLYVM

[0313] SEQ ID NO: 31 (Cfa-N)

[0314] CLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGFVYTQPIAQWHNRGEQEVFEYCLEDGSIIRATKDHKFMTTDGQMLPIDEIFERGLDLKQVDGLP

[0315] SEQ ID NO: 32 (Cfa-C)

[0316] MVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASN

[0317] SEQ ID NO: 33 (Gp41-1-N)

[0318] CLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0319] SEQ ID NO: 34 (Gp41-1-C)

[0320] MMLKKILKIEELDERELIDIEVSGNHLFYANDILTHN

[0321] SEQ ID NO: 35 (IMPDH-l-N)

[0322] CFVPGTLVNTENGLKKIEEIKVGDKVFSHTGKLQEVVDTLIFDRDEEnSINGIDC TKNHEFYVIDKENANRVNEDNIHLFARWVHAEELDMKKHLLIELE

[0323] SEQ ID NO: 36 (IMPDH-l-C)

[0324] MKFKLKEIT SIETKHYKGKVHDLTVNQDHS YNVRGT VVHN

[0325] SEQ ID NO:37 (Nucleotide Sequence of Opt Dys-N)(pZC501)

[0326] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCCTTTTGAAGTGGCAGCGCCTCACCGAGGAACAGTGTCTCTTCAGTGCTTGGCTCTCAGAGAAAGAAGACGCAGTGAACAAGATCCACACGACGGGTTTTAAGGATCAGAACGAAATGCTCAGCAGCCTCCAAAAACTGGCGGTCCTCAAGGCGGACTTGGAGAAGAAGAAGCAAAGCATGGGGAAGCTATATAGCCTGAAGCAAGACCTGTTGTCTACACTGAAAAATAAGTCTGTAACCCAAAAGACGGAAGCCTGGCTTGACAATTTCGCCAGATGCTGGGACAACCTGGTGCAGAAGCTGGAAAAGTCTACTGCGCAGATCAGCCAGGCAGTGACCACCACGCAACCTAGCCTGACCCAGACGACAGTCATGGAAACTGTGACAACCGTCACCACCAGAGAACAGATCCTCGTGAAACATGCCCAGGAAGAACTACCTCCACCACCTCCTCAAAAGAAACGGCAGATCACCGTTGACAGCGAGATTAGAAAAAGATTGGACGTTGATATCACGGAATTGCACTCCTGGATTACACGGTCCGAGGCCGTGCTTCAAAGCCCTGAGTTTGCTATCTTCAGAAAGGAGGGTAATTTTTCCGACCTCAAGGAGAAGGTGAATGCCATTGAGCGGGAGAAGGCTGAGAAATTCAGAAAACTTCAGGATGCAAGCAGGAGCGCCCAGGCACTGGTGGAGCAAATGGTGAACGAGGGTGTGAACGCAGATTCCATCAAACAGGCTTCAGAGCAACTGAACTCGCGGTGGATCGAATTCTGCCAGCTGCTGAGTGAGAGGCTGAACTGGCTGGAGTACCAGAACAACATCATCGCGTTCTACAACCAGCTGCAGCAGCTGGAACAAATGACCACCACCGCCGAGAATTGGCTGAAGATTCAGCCGACAACCCCTTCTGAGCCCACAGCGATAAAAAGTCAGCTGAAAATCTGCAAAGATGAAGTTAACAGGCTGTCCGGACTGCAGCCACAGATCGAGAGGCTCAAGATCCAGAGCATCGCCCTGAAAGAGAAGGGACAGGGTCCTATGTTCCTCGATGCTGACTTTGTGGCTTTCACGAATCACTTCAAGCAGGTCTTTAGCGACGTTCAAGCCAGAGAGAAGGAGCTGCAGACTATCTTTGATACTCTGCCTCCCATGAGGTACCAAGAGACCATGTCAGCCATCCGCACCTGGGTCCAGCAGTCCGAGACTAAACTTAGTATCCCCCAACTGAGCGTGACAGATTACGAAATAATGGAACAAAGACTGGGCGAGCTGCAGGCGCTGCAGAGCAGCCTGCAAGAGCAGCAGAGCGGCCTCTACTATCTGAGCACTACCGTCAAAGAGATGTCTAAGAAGGCCCCTTCAGAGATAAGCCGAAAGTATCAGTCAGAGTTCGAAGAAATAGAGGGCAGGTGGAAGAAGCTGAGCAGCCAGCTTGTGGAGCACTGCCAAAAGTTGGAAGAGCAAATGAACAAGCTTCGGAAGATTCAGAACCATATCCAAACACTGAAAAAGTGGATGGCTGAAGTGGATGTGTTCCTGAAGGAAGAGTGGCCTGCCCTGGGAGACTCAGAGATCCTGAAGAAGCAGCTGAAGCAGTGCAGGCTGCTCGTGAGCGACATCCAAACCATCCAGCCAAGCCTGAACAGCGTGAATGAAGGTGGCCAGAAGATAAAGAATGAGGCAGAGCCTGAATTTGCCTCCAGACTGGAGACTGAACTGAAAGAGCTCAATACTCAGTGGGATCACATGTGTCAGCAGGTGTATGCCCGGAAGGAGGCTCTGAAAGGGGGCCTCGAGAAGACCGTGAGCCTCCAGAAAGACCTGAGCGAGATGCATGAGTGGATGACTCAGGCCGAAGAGGAATACCTGGAGAGAGACTTCGAGTATAAGACACCTGATGAGCTCCAGAAGGCTGTTGAAGAGATGAAGCGAGCCAAAGAGGAAGCGCAGCAGAAGGAAGCCAAAGTTAAGTTACTGACTGAAAGCGTGAACTCAGTAATCGCTCAGGCCCCGCCTGTGGCACAGGAAGCCTTGAAGAAGGAACTGGAGACCCTCACAACAAACTACCAGTGGTTGTGCACTCGGCTGAACGGAAAATGCAAGACCCTGGAAGAGGTCTGGGCATGCTTGTCCTATGATACAGAGATCCTGACCGTGGAATACGGCTTCTTGCCCATAGGTAAAATCGTGGAAGAACGGATTGAATGTACTGTCTACACTGTGGATAAAAATGGCTTTGTGTACACCCAACCGATTGCCCAATGGCACAACCGGGGAGAGCAGGAAGTATTTGAATACTGCCTGGAAGATGGCAGCATCATCAGGGCCACCAAGGATCACAAGTTTATGACCACCGATGGCCAGATGTTGCCCATCGATGAAATTTTCGAGAGGGGCCTGGATCTGAAGCAGGTGGACGGTTTACCTtaa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0327] SEQ ID NO:38 (amino acid sequence of the transgene for Opt Dys-Nl)( pZCSOl)

[0328] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKL SEDEETEVQEQMNLLNSRWECLRVA SMEKQ SNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKED AVNKIHTTGFKDQNEML S SLQKL AVLKADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVDSEIRKRLDVDITELHSWITRSEAVLQSPEFAIFRKEGNFSDLKEKVNAIEREKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKICKDEVNRL SGLQPQIERLKIQ SIALKEKGQGPMFLD ADF VAFTNHFKQ VF SD VQ AREKELQTIFDTLPPMRYQETMS AIRTWVQQ SETKL SIPQLS VTD YEIMEQRLGELQ ALQ S SLQEQQSGLYYLSTTVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKKWMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKDLSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVAQEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGFVYTQPIAQWHNRGEQEVFEYCLEDGSIIRATKDHKFMTTDGQMLPIDEIFERGLDLKQVDGLP

[0329] SEQ ID NO:39 (Nucleotide sequence of Opt Dys-Nl used in ZD101)( pZC503)

[0330] Promoter:GGCCGTCCGCCTTCGGCACCATCCTCACGACACCCAAATATGGCGACGGGTGAGGAATGGTGGGGAGTTATTTTTAGAGCGGTGAGGAAGGTGGGCAGGCAGCAGGTGTTGGCGCTCTAAAAATAACTCCCGGGAGTTATTTTTAGAGCGGAGGAATGGTGGACACCCAAATATGGCGACGGTTCCTCACCCGTCGCCATATTTGGGTGTCCGCCCTCGGCCGGGGCCGCATTCCTGGGGGCCGGGCGGTGCTCCCGCCCGCCTCGATAAAAGGCTCCGGGGCCGGCGGCGGCCCACGAGCTACCCGGAGGAGCGGGAGgctagccaccTransgene is the same as pZC501 :ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCCTTTTGAAGTGGCAGCGCCTCACCGAGGAACAGTGTCTCTTCAGTGCTTGGCTCTCAGAGAAAGAAGACGCAGTGAACAAGATCCACACGACGGGTTTTAAGGATCAGAACGAAATGCTCAGCAGCCTCCAAAAACTGGCGGTCCTCAAGGCGGACTTGGAGAAGAAGAAGCAAAGCATGGGGAAGCTATATAGCCTGAAGCAAGACCTGTTGTCTACACTGAAAAATAAGTCTGTAACCCAAAAGACGGAAGCCTGGCTTGACAATTTCGCCAGATGCTGGGACAACCTGGTGCAGAAGCTGGAAAAGTCTACTGCGCAGATCAGCCAGGCAGTGACCACCACGCAACCTAGCCTGACCCAGACGACAGTCATGGAAACTGTGACAACCGTCACCACCAGAGAACAGATCCTCGTGAAACATGCCCAGGAAGAACTACCTCCACCACCTCCTCAAAAGAAACGGCAGATCACCGTTGACAGCGAGATTAGAAAAAGATTGGACGTTGATATCACGGAATTGCACTCCTGGATTACACGGTCCGAGGCCGTGCTTCAAAGCCCTGAGTTTGCTATCTTCAGAAAGGAGGGTAATTTTTCCGACCTCAAGGAGAAGGTGAATGCCATTGAGCGGGAGAAGGCTGAGAAATTCAGAAAACTTCAGGATGCAAGCAGGAGCGCCCAGGCACTGGTGGAGCAAATGGTGAACGAGGGTGTGAACGCAGATTCCATCAAACAGGCTTCAGAGCAACTGAACTCGCGGTGGATCGAATTCTGCCAGCTGCTGAGTGAGAGGCTGAACTGGCTGGAGTACCAGAACAACATCATCGCGTTCTACAACCAGCTGCAGCAGCTGGAACAAATGACCACCACCGCCGAGAATTGGCTGAAGATTCAGCCGACAACCCCTTCTGAGCCCACAGCGATAAAAAGTCAGCTGAAAATCTGCAAAGATGAAGTTAACAGGCTGTCCGGACTGCAGCCACAGATCGAGAGGCTCAAGATCCAGAGCATCGCCCTGAAAGAGAAGGGACAGGGTCCTATGTTCCTCGATGCTGACTTTGTGGCTTTCACGAATCACTTCAAGCAGGTCTTTAGCGACGTTCAAGCCAGAGAGAAGGAGCTGCAGACTATCTTTGATACTCTGCCTCCCATGAGGTACCAAGAGACCATGTCAGCCATCCGCACCTGGGTCCAGCAGTCCGAGACTAAACTTAGTATCCCCCAACTGAGCGTGACAGATTACGAAATAATGGAACAAAGACTGGGCGAGCTGCAGGCGCTGCAGAGCAGCCTGCAAGAGCAGCAGAGCGGCCTCTACTATCTGAGCACTACCGTCAAAGAGATGTCTAAGAAGGCCCCTTCAGAGATAAGCCGAAAGTATCAGTCAGAGTTCGAAGAAATAGAGGGCAGGTGGAAGAAGCTGAGCAGCCAGCTTGTGGAGCACTGCCAAAAGTTGGAAGAGCAAATGAACAAGCTTCGGAAGATTCAGAACCATATCCAAACACTGAAAAAGTGGATGGCTGAAGTGGATGTGTTCCTGAAGGAAGAGTGGCCTGCCCTGGGAGACTCAGAGATCCTGAAGAAGCAGCTGAAGCAGTGCAGGCTGCTCGTGAGCGACATCCAAACCATCCAGCCAAGCCTGAACAGCGTGAATGAAGGTGGCCAGAAGATAAAGAATGAGGCAGAGCCTGAATTTGCCTCCAGACTGGAGACTGAACTGAAAGAGCTCAATACTCAGTGGGATCACATGTGTCAGCAGGTGTATGCCCGGAAGGAGGCTCTGAAAGGGGGCCTCGAGAAGACCGTGAGCCTCCAGAAAGACCTGAGCGAGATGCATGAGTGGATGACTCAGGCCGAAGAGGAATACCTGGAGAGAGACTTCGAGTATAAGACACCTGATGAGCTCCAGAAGGCTGTTGAAGAGATGAAGCGAGCCAAAGAGGAAGCGCAGCAGAAGGAAGCCAAAGTTAAGTTACTGACTGAAAGCGTGAACTCAGTAATCGCTCAGGCCCCGCCTGTGGCACAGGAAGCCTTGAAGAAGGAACTGGAGACCCTCACAACAAACTACCAGTGGTTGTGCACTCGGCTGAACGGAAAATGCAAGACCCTGGAAGAGGTCTGGGCATGCTTGTCCTATGATACAGAGATCCTGACCGTGGAATACGGCTTCTTGCCCATAGGTAAAATCGTGGAAGAACGGATTGAATGTACTGTCTACACTGTGGATAAAAATGGCTTTGTGTACACCCAACCGATTGCCCAATGGCACAACCGGGGAGAGCAGGAAGTATTTGAATACTGCCTGGAAGATGGCAGCATCATCAGGGCCACCAAGGATCACAAGTTTATGACCACCGATGGCCAGATGTTGCCCATCGATGAAATTTTCGAGAGGGGCCTGGATCTGAAGCAGGTGGACGGTTTACCTtaa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0331] SEQ ID NO:40 (Opt Dys-Nl used in ZD101) amino acid sequence of the transgene(same as pZC501))( pZC503)

[0332] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKL SEDEETEVQEQMNLLNSRWECLRVA SMEKQ SNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKED AVNKIHTTGFKDQNEML S SLQKL AVLKADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVDSEIRKRLDVDITELHSWITRSEAVLQSPEFAIFRKEGNFSDLKEKVNAIEREKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWLEYQNNIIAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKICKDEVNRL SGLQPQIERLKIQ SIALKEKGQGPMFLD ADF VAFTNHFKQ VF SD VQ AREKELQTIFDTLPPMRYQETMS AIRTWVQQ SETKL SIPQLS VTD YEIMEQRLGELQ ALQ S SLQEQQSGLYYLSTTVKEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKKWMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEPEFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKDLSEMHEWMTQAEEEYLERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVAQEALKKELETLTTNYQWLCTRLNGKCKTLEEVWACLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGFVYTQPIAQWHNRGEQEVFEYCLEDGSIIRATKDHKFMTTDGQMLPIDEIFERGLDLKQVDGLP

[0333] SEQ ID NO: 41 ((Opt Dys-M3) nucleotide sequence) (pZC504)

[0334] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGGTGAAGATCATTAGCAGAAAGTCTCTGGGTACTCAGAATGTGTACGATATCGGGGTGGAAAAGGACCACAATTTCCTCCTCAAGAATGGCCTCGTGGCAAGTAATTGCTGGCACGAGCTGCTGTCCTACTTGGAGAAAGCCAACAAATGGTTGAATGAAGTCGAGTTCAAACTCAAGACCACAGAGAATATCCCTGGTGGCGCCGAAGAAATCAGCGAGGTGTTGGACAGCCTGGAGAACCTCATGCGTCACAGCGAAGATAATCCGAACCAAATCAGAATCCTTGCCCAGACCCTGACGGACGGAGGAGTAATGGATGAGCTGATCAATGAGGAACTAGAGACCTTTAATAGCCGCTGGCGTGAGCTTCATGAGGAGGCCGTCCGGCGGCAGAAATTATTGGAGCAGTCCATTCAGTCAGCCCAGGAAACAGAGAAGAGTCTGCACCTCATCCAGGAATCTCTGACCTTCATTGACAAGCAGTTAGCCGCCTACATCGCCGACAAAGTAGATGCTGCTCAAATGCCGCAGGAGGCGCAGAAGATTCAGAGCGACCTGACGAGCCATGAAATTTCTCTCGAGGAAATGAAAAAGCATAACCAAGGAAAAGAAGCTGCCCAGCGAGTGCTGTCACAGATAGATGTGGCTCAAAAGAAGCTGCAGGACGTTAGCATGAAGTTCCGACTGTTCCAGAAACCTGCAAACTTTGAGCAGAGACTGCAAGAGTCAAAAATGATTCTGGACGAAGTGAAGATGCATTTACCTGCCTTAGAAACGAAATCGGTGGAGCAGGAAGTGGTCCAGAGCCAACTGAACCACTGTGTCAACCTGTACAAGAGCCTGAGTGAAGTTAAGTCCGAAGTGGAGATGGTGATCAAGACAGGCCGGCAGATCGTTCAAAAAAAGCAAACCGAAAACCCCAAAGAACTTGATGAGCGGGTGACAGCCTTAAAACTGCACTACAACGAACTGGGCGCTAAGGTGACTGAGAGAAAACAACAGCTGGAGAAGTGCCTGAAACTGAGCAGAAAGATGCGCAAGGAAATGAATGTGCTGACTGAGTGGCTCGCGGCTACAGACATGGAGCTAACAAAGAGATCGGCTGTGGAAGGCATGCCTTCGAATCTAGACTCTGAGGTAGCCTGGGGTAAGGCAACCCAGAAAGAGATTGAGAAGCAGAAGGTCCACCTGAAGAGTATTACAGAAGTGGGAGAGGCTCTAAAAACCGTACTTGGAAAGAAAGAGACATTGGTAGAGGACAAGCTCTCTCTGCTGAATAGCAATTGGATTGCAGTGACCTCGAGAGCTGAAGAATGGCTGAACCTGCTGTTGGAATATCAGAAGCACATGGAAACCTTTGACCAAAATGTGGACCACATTACCAAGTGGATCATCCAGGCTGACACACTGCTAGATGAAAGCGAGAAGAAAAAACCTCAGCAGAAAGAGGACGTTCTGAAGCGACTGAAAGCCGAGCTCAATGACATAAGACCCAAGGTGGACAGCACTCGGGACCAGGCGGCCAATCTGATGGCTAAtCATGGTGATCACTGCAGAAAGCTCGTGGAGCCCCAGATCTCCGAGTTAAATCACCGTTTTGCCGCCATTAGTCACAGGATTAAGACTGGGAAAGCCAGCATCCCACTAAAAGAGCTGGAGCAGTTTAACTCAGATATTCAGAAGCTCCTGGAACCCCTTGAGGCGGAGATCCAGCAGGGTGTAAATCTCAAGGAAGAAGACTTCAACAAAGATATGAACGAAGACAACGAGGGCACAGTTAAGGAACTGCTGCAGAGAGGGGACAACCTACAGCAGCGCATCACAGATGAAAGAAAGAGAGAAGAGATCAAAATAAAGCAACAATTGCTGCAGACCAAACACAACGCACTCAAGGATCTCCGGTCCCAGCGGCGCAAAAAGGCCCTGGAGATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCggtTGCTTCGTGCCCGGTACATTAGTAAACACTGAAAATGGACTAAAAAAGATAGAGGAGATCAAAGTAGGCGACAAGGTCTTCTCTCACACTGGAAAGCTGCAGGAGGTAGTGGACACCCTCATCTTCGACCGGGACGAAGAGATAATCTCTATCAACGGCATCGACTGCACCAAAAACCATGAGTTCTATGTGATCGATAAAGAAAACGCTAACAGAGTGAACGAAGATAACATCCATCTGTTTGCAAGATGGGTGCACGCAGAAGAACTGGACATGAAGAAGCACCTGCTGATAGAACTGGAAtaa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0335] SEQ ID NO:42 ((Opt Dys-M3) amino acid sequence of the transgene)( pZC504)

[0336] MVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGGCFVPGTLVNTENGLKKIEEIKVGDKVFSHTGKLQEVVDTLIFDRDEEIISINGIDCTKNHEFYVIDKENANRVNEDNIHLFARWVHAEELDMKKHLLIELE

[0337] SEQ ID NO:43 (nucleotide sequence of Dys-N for dual vector assembly) ( pZC508)

[0338] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCGGTTGCTTCGTGCCCGGTACATTAGTAAACACTGAAAATGGACTAAAAAAGATAGAGGAGATCAAAGTAGGCGACAAGGTCTTCTCTCACACTGGAAAGCTGCAGGAGGTAGTGGACACCCTCATCTTCGACCGGGACGAAGAGATAATCTCTATCAACGGCATCGACTGCACCAAAAACCATGAGTTCTATGTGATCGATAAAGAAAACGCTAACAGAGTGAACGAAGATAACATCCATCTGTTTGCAAGATGGGTGCACGCAGAAGAACTGGACATGAAGAAGCACCTGCTGATAGAACTGGAAtaapolyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0339] SEQ ID NO:44 (amino acid sequence of the Dys-N transgene for dual vector assembly) ( pZC508)

[0340] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKW YLKELQDGIGQRQTVVRTLNATGEEIIQQ S SKID ASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGGCFVPGTLVNTENGLKKIEEIKVGDKVFSHTGKLQEVVDTLIFDRDEEIISINGIDCTI<NHEFYVIDI<ENANRVKEDNIHLFARWVHAEELDMI<I<HLLIELE

[0341] SEQ ID NO:45 (Dys_M5 nucleotide sequence)( pZCSIO)

[0342] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCGGTTGCTTCGTGCCCGGTACATTAGTAAACACTGAAAATGGACTAAAAAAGATAGAGGAGATCAAAGTAGGCGACAAGGTCTTCTCTCACACTGGAAAGCTGCAGGAGGTAGTGGACACCCTCATCTTCGACCGGGACGAAGAGATAATCTCTATCAACGGCATCGACTGCACCAAAAACCATGAGTTCTATGTGATCGATAAAGAAAACGCTAACAGAGTGAACGAAGATAACATCCATCTGTTTGCAAGATGGGTGCACGCAGAAGAACTGGACATGAAGAAGCACCTGCTGATAGAACTGGAAtaa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0343] SEQ ID NO:46 (Dys_M5 amino acid sequence of the transgene)( pZC510)

[0344] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKL SEDEETEVQEQMNLLNSRWECLRVA SMEKQ SNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDnHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKW YLKELQDGIGQRQTVVRTLNATGEEIIQQ S SKID ASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGGCFVPGTLVNTENGLKKIEEIKVGDKVFSHTGKLQEVVDTLIFDRDEEIISINGIDCTKNHEFYVIDKENANRVNEDNIHLFARWVHAEELDMKKHLLIELE

[0345] SEQ ID NO:47 (Dys_C7 nucleotide sequence)( pZC511)

[0346] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene: atgAAATTCAAACTGAAAGAGATCACCAGCATCGAAACCAAACACTATAAAGGCAAAGTTCATGATCTGACCGTGAATCAGGATCATAGCTATAACGTTCGTGGCACCGTTGTTCATAACTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAA polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0347] SEQ ID NO: 48 (Dys_C7 amino acid sequence of the transgene)(pZC511)

[0348] MKFKLKEITSIETKHYKGKVHDLTVNQDHSYNVRGTVVHNSPTQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEAS SDQWKRLHL SLQELL VWLQLKDDEL SRQ APIGGDFPA VQKQND VHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRF S AYR! AMKLRRLQKALCLDLL SL S AACD ALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLP VQTVLEGDNMETP VTLINF WP VD S AP AS SPQL SHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQ AEYDRLKQQHEHKGLSPLP SPPEMMPT SPQ SPRD AELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0349] SEQ ID NO:49 (modified Dys-C5 with PB29 nucleotide sequence)(pZC517)

[0350] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene: atgcacagctggaacttcaagctgtacgtc AT GAT GCTC AAGAAGAT C C TC AAGATT GAAGAGTT GGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTCCTACTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAA polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0351] SEQ ID NO:50 (modifed Dys_C5 with PB29 amino acid sequence of the transgene)( pZC517)

[0352] MHSWNFKLYVMMLKKILKIEELDERELIDIEVSGNHLFYANDILTHNSPTQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITE TKQLAKDLRQWQTNVDVANDLALKLLRDYS ADD TRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLID SLQDHLEK VK ALRGEIAPLKENVSHVNDLARQLTTLGIQL SP YNL STLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERIL ADLEEENRNLQ AE YDRLKQQHEHKGL SPLPSPPEMMPT SPQ SPRD AELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSD S SQPMLLRVVGSQTSD SMGEEDLL SPPQDT STGLEEVMEQLNNSFP S SRGRNTPGKPMREDTM

[0353] SEQ ID NO:51 (Dys_M5 + PB29 nucleotide sequence)] pZC519)

[0354] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene: atgcacagctggaacttcaagctgtacgtc AT GGT GAAGATC ATT AGC AGAAAGTCTC T GGGT AC TC AGAATGTGTACGATATCGGGGTGGAAAAGGACCACAATTTCCTCCTCAAGAATGGCCTCGTGGCAAGTAATTGCTGGCACGAGCTGCTGTCCTACTTGGAGAAAGCCAACAAATGGTTGAATGAAGTCGAGTTCAAACTCAAGACCACAGAGAATATCCCTGGTGGCGCCGAAGAAATCAGCGAGGTGTTGGACAGCCTGGAGAACCTCATGCGTCACAGCGAAGATAATCCGAACCAAATCAGAATCCTTGCCCAGACCCTGACGGACGGAGGAGTAATGGATGAGCTGATCAATGAGGAACTAGAGACCTTTAATAGCCGCTGGCGTGAGCTTCATGAGGAGGCCGTCCGGCGGCAGAAATTATTGGAGCAGTCCATTCAGTCAGCCCAGGAAACAGAGAAGAGTCTGCACCTCATCCAGGAATCTCTGACCTTCATTGACAAGCAGTTAGCCGCCTACATCGCCGACAAAGTAGATGCTGCTCAAATGCCGCAGGAGGCGCAGAAGATTCAGAGCGACCTGACGAGCCATGAAATTTCTCTCGAGGAAATGAAAAAGCATAACCAAGGAAAAGAAGCTGCCCAGCGAGTGCTGTCACAGATAGATGTGGCTCAAAAGAAGCTGCAGGACGTTAGCATGAAGTTCCGACTGTTCCAGAAACCTGCAAACTTTGAGCAGAGACTGCAAGAGTCAAAAATGATTCTGGACGAAGTGAAGATGCATTTACCTGCCTTAGAAACGAAATCGGTGGAGCAGGAAGTGGTCCAGAGCCAACTGAACCACTGTGTCAACCTGTACAAGAGCCTGAGTGAAGTTAAGTCCGAAGTGGAGATGGTGATCAAGACAGGCCGGCAGATCGTTCAAAAAAAGCAAACCGAAAACCCCAAAGAACTTGATGAGCGGGTGACAGCCTTAAAACTGCACTACAACGAACTGGGCGCTAAGGTGACTGAGAGAAAACAACAGCTGGAGAAGTGCCTGAAACTGAGCAGAAAGATGCGCAAGGAAATGAATGTGCTGACTGAGTGGCTCGCGGCTACAGACATGGAGCTAACAAAGAGATCGGCTGTGGAAGGCATGCCTTCGAATCTAGACTCTGAGGTAGCCTGGGGTAAGGCAACCCAGAAAGAGATTGAGAAGCAGAAGGTCCACCTGAAGAGTATTACAGAAGTGGGAGAGGCTCTAAAAACCGTACTTGGAAAGAAAGAGACATTGGTAGAGGACAAGCTCTCTCTGCTGAATAGCAATTGGATTGCAGTGACCTCGAGAGCTGAAGAATGGCTGAACCTGCTGTTGGAATATCAGAAGCACATGGAAACCTTTGACCAAAATGTGGACCACATTACCAAGTGGATCATCCAGGCTGACACACTGCTAGATGAAAGCGAGAAGAAAAAACCTCAGCAGAAAGAGGACGTTCTGAAGCGACTGAAAGCCGAGCTCAATGACATAAGACCCAAGGTGGACAGCACTCGGGACCAGGCGGCCAATCTGATGGCTAAtCATGGTGATCACTGCAGAAAGCTCGTGGAGCCCCAGATCTCCGAGTTAAATCACCGTTTTGCCGCCATTAGTCACAGGATTAAGACTGGGAAAGCCAGCATCCCACTAAAAGAGCTGGAGCAGTTTAACTCAGATATTCAGAAGCTCCTGGAACCCCTTGAGGCGGAGATCCAGCAGGGTGTAAATCTCAAGGAAGAAGACTTCAACAAAGATATGAACGAAGACAACGAGGGCACAGTTAAGGAACTGCTGCAGAGAGGGGACAACCTACAGCAGCGCATCACAGATGAAAGAAAGAGAGAAGAGATCAAAATAAAGCAACAATTGCTGCAGACCAAACACAACGCACTCAAGGATCTCCGGTCCCAGCGGCGCAAAAAGGCCCTGGAGATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0355] SEQ ID NO:52 (Dys_M5 + PB29 amino acid sequence of the transgene)( pZC519)

[0356] MHSWNFKLYVMVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKD SLQQ S SGRIDIIHSKKT AALQ S ATP VERVKLQEAL SQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWL SPIRNQLEIYNQPNQEGPFD VKETEIAVQ AKQPD VEEIL SKGQHL YKEKP ATQPVKRKLEDL S SEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQ VQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0357] SEQ ID NO: 53 (nucleotide sequence for Dys-M used in ZD101)( pZC520)

[0358] Promoter:GGCCGTCCGCCTTCGGCACCATCCTCACGACACCCAAATATGGCGACGGGTGAGGAATGGTGGGGAGTTATTTTTAGAGCGGTGAGGAAGGTGGGCAGGCAGCAGGTGTTGGCGCTCTAAAAATAACTCCCGGGAGTTATTTTTAGAGCGGAGGAATGGTGGACACCCAAATATGGCGACGGTTCCTCACCCGTCGCCATATTTGGGTGTCCGCCCTCGGCCGGGGCCGCATTCCTGGGGGCCGGGCGGTGCTCCCGCCCGCCTCGATAAAAGGCTCCGGGGCCGGCGGCGGCCCACGAGCTACCCGGAGGAGCGGGAGgctagccaccTransgene; atgcacagctggaacttcaagctgtacgtcATGGTGAAGATCATTAGCAGAAAGTCTCTGGGTACTCAGAATGTGTACGATATCGGGGTGGAAAAGGACCACAATTTCCTCCTCAAGAATGGCCTCGTGGCAAGTAATTGCTGGCACGAGCTGCTGTCCTACTTGGAGAAAGCCAACAAATGGTTGAATGAAGTCGAGTTCAAACTCAAGACCACAGAGAATATCCCTGGTGGCGCCGAAGAAATCAGCGAGGTGTTGGACAGCCTGGAGAACCTCATGCGTCACAGCGAAGATAATCCGAACCAAATCAGAATCCTTGCCCAGACCCTGACGGACGGAGGAGTAATGGATGAGCTGATCAATGAGGAACTAGAGACCTTTAATAGCCGCTGGCGTGAGCTTCATGAGGAGGCCGTCCGGCGGCAGAAATTATTGGAGCAGTCCATTCAGTCAGCCCAGGAAACAGAGAAGAGTCTGCACCTCATCCAGGAATCTCTGACCTTCATTGACAAGCAGTTAGCCGCCTACATCGCCGACAAAGTAGATGCTGCTCAAATGCCGCAGGAGGCGCAGAAGATTCAGAGCGACCTGACGAGCCATGAAATTTCTCTCGAGGAAATGAAAAAGCATAACCAAGGAAAAGAAGCTGCCCAGCGAGTGCTGTCACAGATAGATGTGGCTCAAAAGAAGCTGCAGGACGTTAGCATGAAGTTCCGACTGTTCCAGAAACCTGCAAACTTTGAGCAGAGACTGCAAGAGTCAAAAATGATTCTGGACGAAGTGAAGATGCATTTACCTGCCTTAGAAACGAAATCGGTGGAGCAGGAAGTGGTCCAGAGCCAACTGAACCACTGTGTCAACCTGTACAAGAGCCTGAGTGAAGTTAAGTCCGAAGTGGAGATGGTGATCAAGACAGGCCGGCAGATCGTTCAAAAAAAGCAAACCGAAAACCCCAAAGAACTTGATGAGCGGGTGACAGCCTTAAAACTGCACTACAACGAACTGGGCGCTAAGGTGACTGAGAGAAAACAACAGCTGGAGAAGTGCCTGAAACTGAGCAGAAAGATGCGCAAGGAAATGAATGTGCTGACTGAGTGGCTCGCGGCTACAGACATGGAGCTAACAAAGAGATCGGCTGTGGAAGGCATGCCTTCGAATCTAGACTCTGAGGTAGCCTGGGGTAAGGCAACCCAGAAAGAGATTGAGAAGCAGAAGGTCCACCTGAAGAGTATTACAGAAGTGGGAGAGGCTCTAAAAACCGTACTTGGAAAGAAAGAGACATTGGTAGAGGACAAGCTCTCTCTGCTGAATAGCAATTGGATTGCAGTGACCTCGAGAGCTGAAGAATGGCTGAACCTGCTGTTGGAATATCAGAAGCACATGGAAACCTTTGACCAAAATGTGGACCACATTACCAAGTGGATCATCCAGGCTGACACACTGCTAGATGAAAGCGAGAAGAAAAAACCTCAGCAGAAAGAGGACGTTCTGAAGCGACTGAAAGCCGAGCTCAATGACATAAGACCCAAGGTGGACAGCACTCGGGACCAGGCGGCCAATCTGATGGCTAAtCATGGTGATCACTGCAGAAAGCTCGTGGAGCCCCAGATCTCCGAGTTAAATCACCGTTTTGCCGCCATTAGTCACAGGATTAAGACTGGGAAAGCCAGCATCCCACTAAAAGAGCTGGAGCAGTTTAACTCAGATATTCAGAAGCTCCTGGAACCCCTTGAGGCGGAGATCCAGCAGGGTGTAAATCTCAAGGAAGAAGACTTCAACAAAGATATGAACGAAGACAACGAGGGCACAGTTAAGGAACTGCTGCAGAGAGGGGACAACCTACAGCAGCGCATCACAGATGAAAGAAAGAGAGAAGAGATCAAAATAAAGCAACAATTGCTGCAGACCAAACACAACGCACTCAAGGATCTCCGGTCCCAGCGGCGCAAAAAGGCCCTGGAGATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0359] SEQ ID NO:54 (amino acid sequence of the transgene for Dys-M used inZD101)(pZC520)

[0360] MHSWNFKLYVMVKIISRKSLGTQNVYDIGVEKDHNFLLKNGLVASNCWHELLSYLEKANKWLNEVEFKLKTTENIPGGAEEISEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINEELETFNSRWRELHEEAVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSDLTSHEISLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESKMILDEVKMHLPALETKSVEQEVVQSQLNHCVNLYKSLSEVKSEVEMVIKTGRQIVQKKQTENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDMELTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDKLSLLNSNWIAVTSRAEEWLNLLLEYQKHMETFDQNVDHITKWIIQADTLLDESEKKKPQQKEDVLKRLKAELNDIRPKVDSTRDQAANLMANHGDHCRKLVEPQISELNHRFAAISHRIKTGKASIPLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQRGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWL SPIRNQLEIYNQPNQEGPFD VKETEIAVQ AKQPD VEEIL SKGQHL YKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0361] SEQ ID NO;55 (nucleotide sequence of Dys-N for dual vector assembly)( pZC521)

[0362] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0363] SEQ ID NO:56 (amino acid sequence of the transgene for Dys-N dual vector assembly)( pZC521)

[0364] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLC AKDFEDLFKQEE SLKNIKD SLQQ S SGRIDIIHSKKTAALQ S ATP VERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKW YLKELQDGIGQRQTVVRTLNATGEEIIQQ S SKID ASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0365] SEQ ID NO:57 (Dys-N nucleotide sequence for dual vector assembly)( pZC522)

[0366] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCCTTTTGAAGTGGCAGCGCCTCACCGAGGAACAGTGTCTCTTCAGTGCTTGGCTCTCAGAGAAAGAAGACGCAGTGAACAAGATCCACACGACGGGTTTTAAGGATCAGAACGAAATGCTCAGCAGCCTCCAAAAACTGGCGGTCCTCAAGGCGGACTTGGAGAAGAAGAAGCAAAGCATGGGGAAGCTATATAGCCTGAAGCAAGACCTGTTGTCTACACTGAAAAATAAGTCTGTAACCCAAAAGACGGAAGCCTGGCTTGACAATTTCGCCAGATGCTGGGACAACCTGGTGCAGAAGCTGGAAAAGTCTACTGCGCAGATCAGCCAGGCAGTGACCACCACGCAACCTAGCCTGACCCAGACGACAGTCATGGAAACTGTGACAACCGTCACCACCAGAGAACAGATCCTCGTGAAACATGCCCAGGAAGAACTACCTCCACCACCTCCTCAAAAGAAACGGCAGATCACCGTTGACAGCGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0367] SEQ ID NO:58 (amino acid sequence of the Dys-N transgene for dual vector assemblyX pZC522)

[0368] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKL SEDEETEVQEQMNLLNSRWECLRVA SMEKQ SNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKED AVNKIHTTGFKDQNEML S SLQKL AVER ADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVDSEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEE SLKNIKD SLQQ S SGRIDIIHSKKT AALQ S ATPVERVKLQE ALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0369] SEQ ID NO:59 (nucleotide sequence for Dys-C used in ZD101) (pZC523)

[0370] Promoter:GGCCGTCCGCCTTCGGCACCATCCTCACGACACCCAAATATGGCGACGGGTGAGGAATGGTGGGGAGTTATTTTTAGAGCGGTGAGGAAGGTGGGCAGGCAGCAGGTGTTGGCGCTCTAAAAATAACTCCCGGGAGTTATTTTTAGAGCGGAGGAATGGTGGACACCCAAATATGGCGACGGTTCCTCACCCGTCGCCATATTTGGGTGTCCGCCCTCGGCCGGGGCCGCATTCCTGGGGGCCGGGCGGTGCTCCCGCCCGCCTCGATAAAAGGCTCCGGGGCCGGCGGCGGCCCACGAGCTACCCGGAGGAGCGGGAGgctagccaccTransgene: atgcacagctggaacttcaagctgtacgtcatgATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTtCTtCTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAA polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0371] SEQ ID NO:60 (amino acid sequence of the Dys-C transgene used in ZD101)(pZC523)

[0372] MHSWNFKLYVMMLKKILKIEELDERELIDIEVSGNHLF YANDILTHNS S SQTVTLVTQPVVTKETAISKLEMPSSLMLEVPALADFNRAWTELTDWLSLLDQVIKSQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQAPIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLID SLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQL SP YNL STLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYEJRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSD S SQPMLLRVVGSQTSD SMGEEDLL SPPQDT STGLEE VMEQLNNSFP S SRGRNTPGKPMREDTM

[0373] SEQ ID NO:61 (nucleotide sequence for modified NFL C) (pZC526)

[0374] Promoter:GCATGCCCACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagcCACCTransgene:ATGGACTACGAGTTTCTTAAGAGTTGGACAGTGGAGGACCTTCAGAAGAGGCTCTTGGCCCTGGACCCCATGATGGAGCAGGAGATTGAAGAGATCCGGCAGAAGTgCCAGTCCAAGCGGCAGCCCATCCTGGATGCCATAGAGGCTAAGggctccggaggatctggaggtagtggcATGCTCAAGAAGATCCTCAAGATTGAAGAGTTGGACGAGCGCGAGCTTATAGACATAGAAGTCAGTGGTAATCACCTTTTCTACGCAAATGACATTTTGACTCACAACTCTtCTtCTCAGACTGTTACTCTGGTGACACAACCTGTGGTTACTAAGGAAACTGCCATCTCCAAACTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGCTTGGACAGAACTTACCGACTGGCTTTCTCTGCTTGATCAAGTTATAAAATCACAGAGGGTGATGGTGGGTGACCTTGAGGATATCAACGAGATGATCATCAAGCAGAAGGCGACAATGCAGGATTTGGAACAGAGGCGTCCCCAGTTGGAAGAACTCATTACCGCTGCCCAAAATTTGAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAATTCAGAATCAGTGGGATGAAGTACAAGAACACCTTCAGAACCGGAGGCAACAGTTGAATGAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAAGAAGCTGAGCAGGTCTTAGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAATCCAAAAGAAAATCACAGAAACCAAGCAGTTGGCCAAAGACCTCCGCCAGTGGCAGACAAATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGATACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATAAAAGGGTGAGTGAGCGAGAGGCTGCTTTGGAAGAAACTCATAGATTACTGCAACAGTTCCCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGTCCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGCTGATGAAACAATGGCAAGACCTCCAAGGTGAAATTGAAGCTCACACAGATGTTTATCACAACCTGGGTGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGTCCTGTTACAAAGACGTTTGGATAACATGAACTTCAAGTGGAGTGAACTTCGGAAAAAGTCTCTCAACATTAGGTCCCATTTGGAAGCCAGTTCTGACCAGTGGAAGCGTCTGCACCTTTCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGCACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCAAGAGGGAATTGAAAACTAAAGAACCTGTAATCATGAGTATTCTTGAGACTGTACGAATATTTCTGACAGAGCAGCCTTTGGAAGGACTAGAGAAACCCTACCAGGAGCCCAGAGAGCTGCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGGTCAATACTGAGTGGGAAAAATTGAACCTGCACTCCGCTGACTGGCAGAGAAAAATAGATGAGACCCTTGAAAGACTCCAGGAACTTCAAGAGGCCACGGATGAGCTGGACCTCAAGCTGCGCCAAGCTGAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACTCTCTCCAAGATCACCTCGAGAAAGTCAAGGCACTTCGAGGAGAAATTGCGCCTCTGAAAGAGAACGTGAGCCACGTCAATGACCTTGCTCGCCAGCTTACCACTTTGGGCATTCAGCTCTCACCGTATAACCTCAGCACTCTGGAAGACCTGAACACCAGATGGAAGCTTCTGCAGGTGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCATCTCAGCACTTTCTTTCCACGTCTGTCCAGGGTCCCTGGGAGAGAGCCATCTCGCCAAACAAAGTGCCCTACTATATCAACCACGAGACTCAAACAACTTGCTGGGACCATCCCAAAATGACAGAGCTCTACCAGTCTTTAGCTGACCTGAATAATGTCAGATTCTCAGCTTATAGGACTGCCATGAAACTCCGAAGACTGCAGAAGGCCCTTTGCTTGGATCTCTTGAGCCTGTCAGCTGCATGTGATGCCTTGGACCAGCACAACCTCAAGCAAAATGACCAGCCCATGGATATCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAACAATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTATGATACGGGACGAACAGGGAGGATCCGTGTCCTGTCTTTTAAAACTGGCATCATTTCCCTGTGTAAAGCACATTTGGAAGACAAGTACAGATACCTTTTCAAGCAAGTGGCAAGTTCAACAGGATTTTGTGACCAGCGCAGGCTGGGCCTCCTTCTGCATGATTCTATCCAAATTCCAAGACAGTTGGGTGAAGTTGCATCCTTTGGGGGCAGTAACATTGAGCCAAGTGTCCGGAGCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGGATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGCAGAAACTGCCAAGCATCAGGCCAAATGTAACATCTGCAAAGAGTGTCCAATCATTGGATTCAGGTACAGGAGTCTAAAGCACTTTAATTATGACATCTGCCAAAGCTGCTTTTTTTCTGGTCGAGTTGCAAAAGGCCATAAAATGCACTATCCCATGGTGGAATATTGCACTCCGACTACATCAGGAGAAGATGTTCGAGACTTTGCCAAGGTACTAAAAAACAAATTTCGAACCAAAAGGTATTTTGCGAAGCATCCCCGAATGGGCTACCTGCCAGTGCAGACTGTCTTAGAGGGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCCTGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTAGCAGGCTAGCAGAAATGGAAAACAGCAATGGATCTTATCTAAATGATAGCATCTCTCCTAATGAGAGCATAGATGATGAACATTTGTTAATCCAGCATTACTGCCAAAGTTTGAACCAGGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTGAGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTGCAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCCGTCCCCTCCTGAAATGATGCCCACCTCTCCCCAGAGTCCCCGGGATGCTGAGCTCATTGCTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTGGAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCAACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTACAGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGACTCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGAGGTGATGGAGCAACTCAACAACTCCTTCCCTAGTTCAAGAGGAAGAAATACCCCTGGAAAGCCAATGAGAGAGGACACAATGTAA polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0375] SEQ ID NO:62 (amino acid sequence of the transgene for modified NFL C)( pZC526)

[0376] MDYEFLKSWTVEDLQKRLLALDPMMEQEIEEIRQKCQSKRQPILDAIEAKGSGGSGGSGMLKKILKIEELDERELIDIEVSGNHLFYANDILTHNSSSQTVTLVTQPVVTKETAISKLEMP S SLMLE VP ALADFNRAWTELTDWL SLLDQ VIK SQRVMVGDLEDINEMIIKQKATMQDLEQRRPQLEELITAAQNLKNKTSNQEARTIITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVLGQARAKLESWKEGPYTVDAIQKKITETKQLAKDLRQWQTNVDVANDLALKLLRDYSADDTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLGENSQKILRSLEGSDDAVLLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHL SLQELL VWLQLKDDEL SRQ APIGGDFP AVQKQND VHRAFKRELKTKEP VIMSILETVRIFLTEQPLEGLEKPYQEPRELPPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLQELQEATDELDLKLRQAEVIKGSWQPVGDLLIDSLQDHLEKVKALRGEIAPLKENVSHVNDLARQLTTLGIQLSPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAISPNKVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLSAACDALDQHNLKQNDQPMDILQIINCLTTIYDRLEQEHNNLVNVPLCVDMCLNWLLNVYDTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIPRQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAAETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPTTSGEDVRDFAKVLKNKFRTKRYFAKHPRMGYLPVQTVLEGDNMETPVTLINFWPVDSAPASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQDSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLPSPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQPQAEAKVNGTTVSSPSTSLQRSDSSQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEEVMEQLNNSFPSSRGRNTPGKPMREDTM

[0377] SEQ ID NO:63 (nucleotide sequence for modified Dys-N for dual vector assembly)(pZC529)

[0378] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaaggatctggaGACTACGAGTTTCTTAAGAGTTGGACAGTGGAGGACCTTCAGAAGAGGCTCTTGGCCCTGGACCCCATGtgcGAGCAGGAGATTGAAGAGATCCGGCAGAAGTACCAGTCCAAGCGGCAGCCCATCCTGGATGCCATAGAGGCTAAGtaapolyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0379] SEQ ID NO:64 (amino acid sequence of the modified Dys-N transgene for dual vector assembly)( pZC529)

[0380] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKW YLKELQDGIGQRQTVVRTLNATGEEIIQQ S SKID ASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKEGSGDYEFLKSWTVEDLQKRLLALDPMCEQEIEEIRQK YQ SKRQPILD A IE AK

[0381] SEQ ID NO:65 (nucleotide sequence for Dys-N construct for dual vector assembly)( pZC530)

[0382] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene:ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCCTTTTGAAGTGGCAGCGCCTCACCGAGGAACAGTGTCTCTTCAGTGCTTGGCTCTCAGAGAAAGAAGACGCAGTGAACAAGATCCACACGACGGGTTTTAAGGATCAGAACGAAATGCTCAGCAGCCTCCAAAAACTGGCGGTCCTCAAGGCGGACTTGGAGAAGAAGAAGCAAAGCATGGGGAAGCTATATAGCCTGAAGCAAGACCTGTTGTCTACACTGAAAAATAAGTCTGTAACCCAAAAGACGGAAGCCTGGCTTGACAATTTCGCCAGATGCTGGGACAACCTGGTGCAGAAGCTGGAAAAGTCTACTGCGCAGATCAGCCAGGCAGTGACCACCACGCAACCTAGCCTGACCCAGACGACAGTCATGGAAACTGTGACAACCGTCACCACCAGAGAACAGATCCTCGTGAAACATGCCCAGGAAGAACTACCTCCACCACCTCCTCAAAAGAAACGGCAGATCACCGTTGACtctgaaATCTCCCATCAGTGGTACCAGTACAAAAGACAAGCAGATGATTTACTGAAGTGTCTGGATGACATAGAGAAGAAaCTAGCCTCACTGCCTGAGCCCAGAGACGAAAGAAAAATTAAGGAGATTGACCGAGAGCTGCAGAAGAAGAAGGAGGAACTGAATGCTGTCCGCAGACAGGCCGAAGGCTTGTCTGAGGATGGCGCCGCaATGGCGGTGGAGCCAACCCAGATCCAACTGAGCAAGAGGTGGAGAGAAATCGAGTCAAAGTTTGCCCAGTTCAGAAGATTAAACTTCGCTCAGATCCACACCGTGCGGGAGGAAACCATGATGGTCATGACGGAAGACATGCCCCTGGAGATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGT C AAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0383] SEQ ID NO:66 (amino acid sequence of the Dys-N transgene for dual vector assembly)( pZC530)

[0384] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPRFKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKSFGSSLMESEVNLDRYQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKED AVNKIHTTGFKDQNEML S SLQKL AVLK ADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVDSEISHQWYQYKRQADDLLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEPTQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

[0385] SEQ ID NO:67 (nucleotide sequence for Dys-N construct for dual vector assembly)( pZC531)

[0386] Promoter:GATGAGAGCAGCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCAGACATGTGGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGCTAAAAATAACCCTGTCCCTGGTGGccctgcatgcccACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCgctagccaccTransgene;ATGCTGTGGTGGGAGGAGGTAGAGGATTGCTACGAAAGAGAGGACGTTCAGAAGAAGACCTTCACCAAATGGGTGAACGCACAGTTTTCCAAGTTTGGAAAGCAGCATATTGAAAACCTGTTCTCCGACCTTCAGGATGGCAGGAGGCTGCTCGATCTGCTCGAGGGGCTGACCGGGCAGAAGCTACCCAAAGAAAAAGGAAGCACCCGTGTACACGCCCTCAACAACGTGAATAAAGCCTTAAGAGTGCTGCAAAACAACAATGTGGACCTGGTGAACATTGGCAGCACCGACATCGTGGACGGAAACCACAAACTGACATTGGGCCTCATCTGGAATATCATTCTGCACTGGCAGGTAAAGAATGTGATGAAGAACATTATGGCCGGCTTGCAGCAGACCAACAGCGAAAAGATCCTGCTGTCGTGGGTGAGACAGAGCACAAGGAACTACCCTCAGGTGAATGTGATCAACTTCACTACCTCTTGGAGTGACGGCCTGGCCTTAAATGCCCTGATCCATTCGCATAGACCAGACCTGTTTGATTGGAACTCCGTGGTGTGTCAGCAAAGTGCCACTCAGAGACTGGAGCACGCATTCAACATCGCTAGATACCAGCTGGGCATTGAGAAACTGTTGGACCCAGAGGATGTGGACACTACATACCCTGACAAGAAATCTATCCTAATGTACATCACTTCTCTGTTCCAAGTGCTGCCTCAACAAGTGAGCATTGAAGCTATCCAGGAAGTGGAGATGCTCCCACGACCGCCAAAGGTGACAAAGGAAGAGCATTTCCAGTTACACCACCAGATGCACTACAGCCAGCAGATTACAGTGTCTCTGGCTCAGGGCTATGAAAGAACCTCCAGCCCCAAACCCCGCTTCAAATCCTACGCATACACACAGGCTGCCTACGTGACGACTTCTGACCCCACCAGAAGCCCATTCCCTAGTCAGCACCTGGAGGCCCCGGAGGATAAAAGCTTCGGCAGCTCCCTGATGGAGTCCGAGGTTAACTTGGACCGCTACCAGACTGCGCTGGAGGAGGTGTTGAGCTGGCTGCTGTCTGCAGAGGACACACTACAGGCTCAAGGAGAAATCTCTAACGATGTTGAGGTTGTGAAGGACCAGTTCCATACCCACGAAGGCTACATGATGGACCTCACCGCCCACCAGGGCAGAGTGGGCAACATTCTGCAACTGGGCAGCAAATTAATTGGCACCGGCAAGCTGTCCGAAGACGAGGAGACAGAAGTTCAGGAACAGATGAATTTACTCAATAGCAGATGGGAATGTCTCCGGGTGGCCTCCATGGAAAAACAGAGCAACCTACACAGAGTTCTGATGGACTTACAGAACCAGAAGCTTAAGGAGCTGAATGACTGGCTGACCAAAACAGAAGAGAGAACAAGAAAGATGGAAGAGGAGCCTCTGGGGCCCGATCTGGAAGACCTCAAGAGGCAGGTACAGCAACACAAGGTGCTGCAGGAAGACCTGGAGCAGGAGCAAGTCCGAGTGAACAGTTTAACCCACATGGTGGTAGTGGTTGACGAGAGTAGCGGAGACCATGCCACAGCCGCCCTGGAAGAACAGCTTAAAGTGCTGGGCGACAGGTGGGCCAACATCTGTCGCTGGACAGAGGACCGGTGGGTCCTACTGCAGGATATCCTTTTGAAGTGGCAGCGCCTCACCGAGGAACAGTGTCTCTTCAGTGCTTGGCTCTCAGAGAAAGAAGACGCAGTGAACAAGATCCACACGACGGGTTTTAAGGATCAGAACGAAATGCTCAGCAGCCTCCAAAAACTGGCGGTCCTCAAGGCGGACTTGGAGAAGAAGAAGCAAAGCATGGGGAAGCTATATAGCCTGAAGCAAGACCTGTTGTCTACACTGAAAAATAAGTCTGTAACCCAAAAGACGGAAGCCTGGCTTGACAATTTCGCCAGATGCTGGGACAACCTGGTGCAGAAGCTGGAAAAGTCTACTGCGCAGATCAGCCAGGCAGTGACCACCACGCAACCTAGCCTGACCCAGACGACAGTCATGGAAACTGTGACAACCGTCACCACCAGAGAACAGATCCTCGTGAAACATGCCCAGGAAGAACTACCTCCACCACCTCCTCAAAAGAAACGGCAGATCACCGTTGACAGCGAGATTAGAAAAAGATTGGACGTTGATATCACGGAATTGCACTCCTGGATTACACGGTCCGAGGCCGTGCTTCAAAGCCCTGAGTTTGCTATCTTCAGAAAGGAGGGTAATTTTTCCGACCTCAAGGAGAAGGTGAATGCCATTGAGCGGGAGAAGGCTGAGAAATTCAGAAAACTTCAGGATGCAAGCAGGAGCGCCCAGGCACTGGTGGAGCAAATGGTGAACGAGGGTGTGAACGCAGATTCCATCAAACAGGCTTCAGAGCAACTGAACTCGCGGTGGATCGAATTCTGCCAGCTGCTGAGTGAGAGGCTGAACTGGCTGGAGTACCAGAACAACATCATCAGCTATGTGCCTTCAACCTACCTGACCGAAATTACCCACGTGTCTCAAGCGTTGTTAGAAGTTGAACAGTTGCTGAACGCCCCAGATCTTTGTGCCAAGGACTTTGAGGACCTATTCAAGCAGGAGGAAAGCCTCAAGAACATCAAAGACTCCCTGCAACAAAGTAGCGGCAGGATCGACATCATTCACTCCAAGAAAACCGCCGCACTGCAAAGTGCCACCCCAGTGGAGAGAGTGAAACTGCAGGAAGCTCTGAGTCAGCTGGACTTCCAGTGGGAAAAGGTTAATAAGATGTACAAAGATCGCCAGGGCAGGTTCGACAGATCGGTGGAGAAGTGGAGAAGGTTTCACTATGACATCAAGATCTTCAACCAGTGGCTGACCGAAGCCGAGCAATTCTTGCGTAAGACACAGATCCCCGAGAACTGGGAGCACGCCAAGTATAAATGGTACCTGAAAGAGCTGCAGGACGGAATCGGGCAAAGGCAGACTGTGGTGAGAACTTTGAACGCCACAGGAGAGGAGATAATTCAGCAGAGCAGCAAAACTGACGCCTCTATCTTACAGGAAAAGCTGGGCAGCCTGAACCTTAGATGGCAGGAGGTCTGCAAACAGCTCTCTGACCGGAAAAAGAGACTGGAGGAACAGAAGAATATCCTCAGCGAGTTCCAGAGGGACCTGAACGAATTTGTGCTGTGGCTAGAAGAGGCCGACAACATTGCTTCCATACCTCTTGAACCTGGGAAAGAGCAGCAGTTGAAAGAGAAGTTGGAGCAGGTGAAGCTCCTGGTGGAAGAACTGCCTCTGCGCCAGGGCCGGATCCTGAAACAGTTAAACGAGACTGGCGGCCCTGTCCTAGTGAGTGCCCCTATCAGCCCAGAGGAACAAGATAAGCTCGAGAACAAGCTGAAACAGACTAATCTGCAGTGGATCAAGGTCAGCCGGGCGCTGCCCGAGAAGCAGGGGGAGATTGAGGCCCAAATCAAGGATCTGGGGCAGCTCGAAAAGAAGCTGGAGGATCTGGAGGAACAACTGAACCACCTGCTACTGTGGTTGTCCCCCATTCGCAACCAGCTGGAGATTTACAACCAGCCCAACCAGGAGGGCCCCTTTGATGTGAAGGAAACCGAAATCGCCGTCCAGGCTAAGCAGCCAGATGTGGAGGAAATCCTCAGCAAGGGACAGCACCTGTATAAGGAAAAGCCAGCCACGCAGCCTGTGAAGCGGAAACTGGAGGACCTATCTAGTGAATGGAAAGCCGTGAACAGGCTGCTGCAGGAGCTGAGAGCCAAGCAACCAGACTTGGCCCCTGGCCTCACCACGATCGGCtacTGTTTGGATCTGAAAACGCAAGTTCAAACGCCACAGGGTATGAAAGAAATATCCAATATACAGGTCGGCGATCTCGTCTTGTCTAACACTGGCTATAACGAGGTGCTGAATGTATTTCCAAAAAGCAAGAAAAAAAGTTACAAGATAACTCTGGAAGATGGAAAAGAAATTATCTGTTCTGAGGAGCATCTGTTTCCGACCCAAACAGGGGAGATGAATATCAGTGGCGGTCTCAAAGAGGGTATGTGTTTGTATGTCAAGGaataa polyA: AATAAAaGATCtTTATTTTCATTaGATCtGTGTGTTGGTTTTTTGTGTG

[0387] SEQ ID NO:68 (amino acid sequence of the Dys-N transgene for dual vector assemblyX pZC531)

[0388] MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTGQKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWQVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHRPDLFDWNSVVCQQSATQRLEHAFNIARYQLGIEKLLDPEDVDTTYPDKKSILMYITSLFQVLPQQVSIEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTS SPKPRFK S Y A YTQ A A YVTT SDPTRSPFP SQHLE APEDK SFGS SLMESEVNLDR YQTALEEVLSWLLSAEDTLQAQGEISNDVEVVKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSEDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTRKMEEEPLGPDLEDLKRQVQQHKVLQEDLEQEQVRVNSLTHMVVVVDESSGDHATAALEEQLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKED AVNKIHTTGFKDQNEML S SLQKL A VLK ADLEKKKQ SMGKL YSLKQDLL STLKNKSVTQKTEAWLDNFARCWDNLVQKLEKSTAQISQAVTTTQPSLTQTTVMETVTTVTTREQILVKHAQEELPPPPPQKKRQITVD SEIRKRLD VDITELHS WITRSEA VLQ SPEF AIFRKEGNF SDLKEK VNAIEREK AEKFRKLQD ASRS AQ AL VEQMVNEGVNAD SIKQ ASEQLNSRWIEFCQLLSERLNWLEYQNNIISYVPSTYLTEITHVSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQSSGRIDIIHSKKTAALQSATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKIFNQWLTEAEQFLRKTQIPENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQEKLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIASIPLEPGKEQQLKEKLEQVKLLVEELPLRQGRILKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQWIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQEGPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQELRAKQPDLAPGLTTIGYCLDLKTQVQTPQGMKEISNIQVGDLVLSNTGYNEVLNVFPKSKKKSYKITLEDGKEIICSEEHLFPTQTGEMNISGGLKEGMCLYVKE

Claims

CLAIMSI claimClaim 1. A system for expressing a full-length dystrophin protein in a cell comprising multiple independent virus vectors encoding fragments of the full-length dystrophin protein, wherein the fragments are trans-spliced by at least one split intein.Claim 2. The system of claim 1, wherein the multiple independent virus vectors comprise:I) a first independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO: 3, or the complement thereof;II) a second independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; andIII) a third independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof.Claim 3. The system of claim 1, wherein the multiple independent virus vectors comprise:I) a first independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:39 or the complement thereof;II) a second independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:53 or the complement thereof; andIII) a third independent vector comprising a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:59 or the complement thereof.Claim 4. The system of any one of claims 1 to 3, wherein at least one of the virus vectors comprises a CMV promoter or a muscle-specific promoter.Claim 5. The system of claim 4, wherein the muscle-specific promoter comprises a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:27 or the complement thereof;or a nucleotide sequence that has at least 90% sequence identity to SEQ ID NO:28 or the complement thereof.Claim 6. The system of any one of claims 1 to 3, wherein the at least one split intein is Cfa, GP41-1, IMPDH-1, or a combination thereof.Claim 7. The system of claim 6, wherein the at least one split intein is Cfa comprising the amino acid sequence of SEQ ID NO:31 and / or SEQ ID NO:32.Claim 8. The system of claim 6, wherein the at least one split intein is GP41-1 comprising the amino acid sequence of SEQ ID NO:33 and / or SEQ ID NO:34.Claim 9. The system of claim 6, wherein the at least one split intein is IMPDH-1 comprising the amino acid sequence of SEQ ID NO:35 and / or SEQ ID NO:36.Claim 10. The system of any one of claims 1 to 3, wherein the virus vector is an adeno- associated virus vector.Claim 11. The system of claim 10, wherein the adeno-associated virus vector is a myotropic adeno-associated virus vector.Claim 12. A triple myotropic adeno-associated virus vector system for expressing a full-length dystrophin protein in a cell comprising:I) a first independent vector comprising a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO: 3;II) a second independent vector comprising a nucleotide sequence encoding an M fragment that has at least 90% to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; andIll) a third independent vector comprising a nucleotide sequence encoding a C fragment that has at least 90% to any one of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof.Claim 13. The system of claim 12, wherein:I) the first independent vector comprises the nucleotide sequence of SEQ ID NO: 3 or the complement thereof;II) the second independent vector comprises the nucleotide sequence of SEQ ID NO: 19 or the complement thereof; andIII) the second independent vector comprises the nucleotide sequence SEQ ID NO: 21 or the complement thereof.Claim 14. The system of any one of claims 1 to 3, wherein the cell is a mammalian cell.Claim 15. The system of claim 14, wherein the mammalian cell is a human cell.Claim 16. The system of any one of claims 1 to 3, wherein the full-length dystrophin protein comprises an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 2.Claim 17. The system of claim 16, wherein the full-length dystrophin protein comprises or consists of the amino acid sequence SEQ ID NO: 2.Claim 18. A pharmaceutical composition comprising the system of any one of claims 1 to 3 and a pharmaceutically acceptable excipient.Claim 19. A method of treating a subject having a dystrophin deficiency, comprising administering the system of any one of claims 1 to 3 or the pharmaceutical composition of claim 18 to the subject.Claim 20. The method of claim 19, wherein the subject has a muscular dystrophy.Claim 21. The method of claim 20, wherein the subject has Duchenne muscular dystrophy(DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, a limb-girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.Claim 22. The method of any one of claims 19 to 21, wherein the subject is a mammal.Claim 23. The method of claim 22, wherein the mammal is human.Claim 24. A method for transducing a cell with the system of any one of claims 1-3.Claim 25. A method for transducing a cell with multiple vectors to produce a full-length dystrophin protein, wherein the cell is transduced with:I) a first independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO: 3;II) a second independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an M fragment that has at least 90% to any one of SEQ ID NO: 5, SEQ ID NO: 9, SEQ ID NO: 19, or the complement thereof; andIII) a third independent myotropic adeno-associated virus vector comprising the nucleotide sequence encoding a C fragment that has at least 90% to any one of SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 21, or the complement thereof; wherein the vg / kg ratio of the first to the second to the third independent myotropic adeno-associated virus vector is 1 : 1 : 1, 1 :2: 1, 1 :2:2, 2: 1 : 1, 2:2: 1, or 2: 1 :2.Claim 26. A method for transducing a cell with multiple vectors to produce a full-length dystrophin protein, wherein the cell is transduced with:I) a first independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an N fragment that has at least 90% sequence identity to SEQ ID NO:39, or the complement thereof; andII) a second independent myotropic adeno-associated virus vector comprising a nucleotide sequence encoding an M fragment that has at least 90% to SEQ ID NO:53, or the complement thereof; andIII) a third independent myotropic adeno-associated virus vector comprising the nucleotide sequence encoding a C fragment that has at least 90% to SEQ ID NO:59, or the complement thereof; wherein the vg / kg ratio of the first to the second to the third independent myotropic adeno-associated virus vector is 1 : 1 : 1 to 1 : 1 : 1.4.Claim 27. The method of claim 25 or 26, wherein the cell is a mammalian cell.Claim 28. The method of claim 27, wherein the mammalian cell is a human muscle cell.Claim 29. A system for expressing a not full-length dystrophin protein in a cell comprising two independent virus vectors encoding fragments of the full-length dystrophin protein, wherein the fragments are trans-spliced by at least one split intein.Claim 30. The system of claim 29, wherein the two independent virus vectors comprise:I) a first independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO: 43, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:63, SEQ ID NO:65 or SEQ ID NO:67, or the complement thereof; andII) a second independent vector comprising a nucleotide sequence that has at least 90% sequence identity to any one of SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 61, or the complement thereof; and

Images