Granted Patent
B2
US 12,337,040 · App. 17/555,233 · Granted Jun 24, 2025
Dystrophin R16/R17 syntrophin PDZ fusion proteins
Inventors:
Dongsheng Duan (Columbia, MO); Yi Lai (Columbia, MO); Junling Zhao (Columbia, MO); Yongping Yue (Columbia, MO)
A61K48/005A61K9/0019A61K35/28A61K48/00A61P25/14C07K14/4716C12N5/0663C12N15/62C12N15/85C12N15/86A61K35/00A61K38/00C07K2319/00C07K2319/01C12N2750/14143
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Abstract
Synthetic nucleic acids encoding mini and microdystrophin genes comprising the membrane binding motifs or domains of the R10-R11-R12 region are provided. Also provided are vectors, host cells, and related methods of using the same to treat a subject suffering from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) or X-linked dilated cardiomyopathy (XLDC), or for ameliorating one or more adverse effects of DMD, BMD, or XLDC. Also provided are a fusion protein comprising a nNOS binding domain of dystrophin R16-R17 that is operably linked to a syntrophin PDZ domain and synthetic nucleic acids comprising the same that can be used to treat subjects with diseases characterized by loss of sarcolemmal neuronal nitric oxide synthase (nNOS) activity.
Claims (25)
1. A synthetic nucleic acid molecule comprising:
(i) a sequence encoding a fusion protein comprising a nNOS binding domain of dystrophin R16-R17 that is operably linked to a syntrophin PDZ domain,
wherein the n-terminal alpha-helix, alpha-helix 2, and alpha-helix 3 of the R16 domain are present in the fusion protein and alpha-helix 1, alpha-helix 2, and alpha-helix 3 of the R17 domain are present in the fusion protein; or
(ii) a sequence encoding a fusion protein comprising a nNOS binding domain of dystrophin R16-R17 that is operably linked to a syntrophin PDZ domain,
wherein the n-terminal alpha helix of the R16 domain (SEQ ID NO: 59) or a portion thereof is substituted in phase with an alpha helix from another dystrophin repeat; and
wherein alpha-helix 2 and alpha-helix 3 of the R16 domain are present in the fusion protein and alpha-helix 1, alpha-helix 2, and alpha-helix 3 of the R17 domain are present in the fusion protein.
2. A composition comprising the synthetic nucleic acid molecule of claim 1 and a pharmaceutically acceptable carrier.
3. An isolated host cell comprising the synthetic nucleic acid molecule of claim 1 .
4. A single recombinant adeno-associated virus (AAV) vector comprising the synthetic nucleic acid molecule of claim 1 , wherein said synthetic nucleic acid molecule is operably linked to an expression cassette and viral inverted terminal repeats (ITRs) in the AAV.
5. A composition comprising the vector of claim 4 and a pharmaceutically acceptable carrier.
6. An isolated host cell comprising the vector of claim 4 .
7. A dual recombinant AAV vector system, comprising two AAV vectors, wherein one of the two AAV vectors comprises a part of the synthetic nucleic acid molecule of claim 1 , and the other vector comprises the remaining part of said synthetic nucleic acid molecule, wherein the two vectors further comprise sequences that permit recombination with each other to produce said nucleic acid in full length, and wherein the nucleic acid in full length is operably linked to an expression cassette and viral ITRs.
8. A composition comprising the vectors of claim 7 and a pharmaceutically acceptable carrier.
9. An isolated host cell comprising the vectors of claim 7 .
10. A lentiviral vector comprising the synthetic nucleic acid molecule of claim 1 , wherein the synthetic nucleic acid molecule is operably linked to an expression cassette, 5′ and 3′ long terminal repeats (LTR), and a psi sequence in the lentiviral vector.
11. A composition comprising the vector of claim 10 and a pharmaceutically acceptable carrier.
12. An isolated host cell comprising the vector of claim 10 .
13. A method of increasing the localization of nNOS to the sarcolemma of a subject having a neuromuscular disorder characterized by loss of sarcolemmal neuronal nitric oxide synthase (nNOS) activity, the method comprising administering to the subject a therapeutically effective amount of the synthetic nucleic acid molecule of claim 1 .
14. The method of claim 13 , wherein the neuromuscular disorder characterized by loss of sarcolemmal nNOS activity is selected from the group consisting of Duchenne muscular dystrophy (DMD), age-related muscle atrophy, and cancer cachexia.
15. The method of claim 13 , wherein the neuromuscular disorder characterized by loss of sarcolemmal nNOS activity is selected from the group consisting A of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDC).
16. The method of claim 13 , wherein the synthetic nucleic acid molecule is administered via a lentiviral vector comprising the synthetic nucleic acid molecule, and wherein the nucleic acid molecule is operably linked to an expression cassette, 5′ and 3′ long terminal repeats (LTR), and a psi sequence in the lentiviral vector.
17. The method of claim 13 , wherein the synthetic nucleic acid molecule is administered via a single recombinant adeno-associated virus (AAV) vector comprising said synthetic nucleic acid molecule, and wherein said nucleic acid molecule is operably linked to an expression cassette and viral inverted terminal repeats (ITRs) in the AAV.
18. The method of claim 13 , wherein a defective endogenous dystrophin gene of the host cell or a defective portion thereof is edited to provide the synthetic nucleic acid molecule within the host cell's X-chromosome.
19. The method of claim 13 , wherein the neuromuscular disorder characterized by loss of sarcolemmal nNOS activity is selected from the group consisting of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).
20. The method of claim 13 , wherein the neuromuscular disorder characterized by loss of sarcolemmal nNOS activity is Duchenne muscular dystrophy (DMD).
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 13, 2022
From: DUAN, DONGSHENG; LAI, YI; ZHAO, JUNLING; YUE, YONGPING
To: THE CURATORS OF THE UNIVERSITY OF MISSOURI
Reel/Frame 060183/0200 →
Continuity (5)
Continuation
16311236
Provisional Application
62367559
· Jul 27, 2016
Provisional Application
62357865
· Jul 1, 2016
Provisional Application
62352927
· Jun 21, 2016
References Cited (127)
US 5580859A
· Felgner et al.
· 1996
[cited by applicant]
US 20040033604A1
· Kobinger et al.
· 2004
[cited by applicant]
US 20080044393A1
· White et al.
· 2008
[cited by applicant]
US 20140140969A1
· Beausejour et al.
· 2014
[cited by applicant]
US 20160153004A1
· Zhang et al.
· 2016
[cited by applicant]
Duan, et al. (2021) “Primer: Duchenne muscular dystrophy”, Nature Reviews, 7:13. (Year: 2021).
[cited by examiner]
Tidball, et al. (2014) “Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy”, Journal of Physiology, DOI: 10.1113/jphysiol,2014,274878, pp. 4627-4638. (Year: 2014).
[cited by examiner]
Banks et al., “Functional capacity of dystrophins carrying deletions in the N-terminal actin-binding domain”, Human Molecular Genetics, 2007, pp. 2105-2113, vol. 16, No. 17.
[cited by applicant]
Boehler et al., “Clinical potential of microdystrophin as a surrogate endpoint”, Neuromuscular Disorders, 2023, pp. 40-49, vol. 33.
[cited by applicant]
Duan, “Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy”, Molecular Therapy, Oct. 2018, pp. 2337-2356, vol. 26, No. 10.
[cited by applicant]
Fabb et al., “Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144 kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nud…
[cited by applicant]
Foster et al., “Codon and mRNA Sequence Optimization of Microdystrophin Transgenes Improves Expression and Physiological Outcome in Dystrophic mdx Mice Following AAV2/8 Gene Transfer”, Molecular Therapy, Nov. 2008, pp. …
[cited by applicant]
Hakim et al., “A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy”, Molecular Therapy: Methods & Clinical Development, 2017, pp. 216-230, v…
[cited by applicant]
JØrgensen et al., “Efficient and Fast Functional Screening of Microdystrophin Constructs In Vivo and In Vitro for Therapy of Duchenne Muscular Dystrophy”, Human Gene Therapy, Jun. 2009, pp. 641-650, vol. 20.
[cited by applicant]
Koo et al., “Delivery of AAV2/9-Microdystrophin Genes Incorporating Helix 1 of the Coiled-Coil Motif in the C-Terminal Domain of Dystrophin Improves Muscle Pathology and Restores the Level of a1-Syntrophin and a-Dystrob…
[cited by applicant]
Sakamoto et al., “Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene”, Biochemical and Biophysical Research Communications, 2002, pp. 1265-1272, vol. 293.
[cited by applicant]
Shin et al., “Improvement of cardiac fibrosis in dystrophic mice by rAAV9-mediated microdystrophin transduction”, Gene Therapy, 2011, pp. 910-919, vol. 18, No. 9.
[cited by applicant]
Yoshimura et al., “AAV Vector-Mediated Microdystrophin Expression in a Relatively Small Percentage of mdx Myofibers Improved the mdx Phenotype”, Molecular Therapy, Nov. 2004, pp. 821-828, vol. 10, No. 5.
[cited by applicant]
Yuasa et al., “Effective restoration of dystrophin-associated proteins in vivo by adenovirus-mediated transfer of truncated dystrophin cDNAs”, FEBS Letters, 1998, pp. 329-336, vol. 425.
[cited by applicant]
“Sequence 137006 from Patent EP1716227”, Database EPO Proteins [Online], Oct. 11, 2013, XP002810809, retrieved from EBI accession No. EP0P:JB557990.
[cited by applicant]
Legardinier et al., “Mapping of the Lipid-Binding and Stability Properties of the Central Rod Domain of Human Dystrophin”, Journal of Molecular Biology, 2009, pp. 546-558, vol. 389.
[cited by applicant]
Legardinier et al., “Sub-Domains of the Dystrophin Rod Domain Display Contrasting Lipid-Binding and Stability Properties”, Biochimica et Biophysica Acta, 2008, pp. 672-682, vol. 1784.
[cited by applicant]
Levitt et al., “Definition of an Efficient Synthetic Poly(A) Site”, Genes & Development, 1989, pp. 1019-1025, vol. 3.
[cited by applicant]
Li et al., “A highly functional mini-dystrophin/GFP fusion gene for cell and gene therapy studies of Duchenne muscular dystrophy”, Human Molecular Genetics, 2006, pp. 1610-1622, vol. 15, No. 10.
[cited by applicant]
Liadaki et al., “Co-Detection of GFP and Dystrophin in Skeletal Muscle Tissue Sections”, Bio Techniques, 2007, pp. 699-700, vol. 42, No. 6.
[cited by applicant]
Linder et al., “Palmitoylation: Policing Protein Stability and Traffic”, Nature Reviews Molecular Cell Biology, 2007, pp. 74-78, vol. 8, No. 1.
[cited by applicant]
Liu et al., “Adeno-Associated Virus-Mediated Microdystrophin Expression Protects Young mdx Muscle from Contraction-Induced Injury”, Mol Ther., 2005, pp. 245-256, vol. 11, No. 2.
[cited by applicant]
Luna et al., “Cytoskeleton-Plasma Membrane Interactions”, Science, 1992, pp. 955-964, vol. 258, No. 5084.
[cited by applicant]
Maconochie et al., “The Cysteine-Rich and C-Terminal Domains of Dystrophin are not Required for Normal Costameric Localization in the Mouse”, Transgenic Research, 1996, pp. 123-130, vol. 5.
[cited by applicant]
Mariani et al., “A Tightly Membrane-Associated Subpopulation of Spectrin Is
[cited by applicant]
Mendell et al., “Dystrophin Immunity in Duchenne's Muscular Dystrophy”, The New England Journal of Medicine, 2010, pp. 1429-1437, vol. 363, No. 15.
[cited by applicant]
Odom et al., “Gene Therapy of mdx Mice with Large Truncated Dystrophins Generated by Recombination Using rAAV6”, Molecular Therapy, 2011, pp. 36-45, vol. 19, No. 1.
[cited by applicant]
Oku et al., “In Silico Screening for Palmitoyl Substrates Reveals a Role for DHHC1/3/10 (zDHHC1/3/11)-Mediated Neurochondrin Palmitoylation in Its Targeting to Rab5-Positive Endosomes”, The Journal of Biological Chemist…
[cited by applicant]
Petrof et al., “Dystrophin Protects the Sarcolemma from Stresses Developed During Muscle Contraction”, Proc. Natl. Acad. Sci. USA, 1993, pp. 3710-3714, vol. 90.
[cited by applicant]
Prior et al., “Spectrum of Small Mutations in the Dystrophin Coding Region”, Am. J. Hum. Genet., 1995, pp. 22-33, vol. 57.
[cited by applicant]
Rafael et al., “Forced Expression of Dystrophin Deletion Constructs Reveals Structure-Function Correlations”, The Journal of Cell Biology, 1996, pp. 93-102, vol. 134, No. 1.
[cited by applicant]
Rapaport et al., “Dp71, the Nonmuscle product of the Duchenne Musuclar Dystrophy Gene is Associated with the Cell Membrane”, FEBS Letters, 1993, pp. 197-202, vol. 328, No. 12.
[cited by applicant]
Recan et al., “Are Cysteine-Rich and COOH-Terminal Domains of Dystrophin Cirical for Sarcolemmal Localization?”, J. Clin. Invest., 1992, pp. 712-716, vol. 89.
[cited by applicant]
Ren et al., “CSS-Palm 2.0: An Updated Software for Palmitoylation Sites Prediction”, Protein Engineering, Design & Selection, 2008, pp. 639-644, vol. 21, No. 11.
[cited by applicant]
Rumeur et al., “Binding of the Dystrophin Second Repeat to Membrane Di-Oleyl Phospholipids is Dependent Upon Lipid Packing”, Biochimica et Biophysica Acta, 2007, pp. 648-654, vol. 1768.
[cited by applicant]
Rumeur et al., “Dystrophin: More Than Just the Sum of its Parts”, Biochimica et Biophysica Acta, 2010, pp. 1713-1722, vol. 1804, No. 9.
[cited by applicant]
Rumeur et al., “Interaction of Dystrophin Rod Domain with Membrane Phospholipids”, The Journal of Biological Chemistry, 2003, pp. 5993-6001, vol. 278, No. 8.
[cited by applicant]
Rybakova et al., “A New Model for the Interaction of Dystrophin with F-Actin”, The Journal of Cell Biology, 1996, pp. 661-672, vol. 135, No. 3.
[cited by applicant]
Sadoulet-Puccio et al., “Dystrobrevin and Dystrophin: An Interaction Through Coiled-Coil Motifs”, Proc. Natl. Acad. Sci. USA, 1997, pp. 12413-12418, vol. 94.
[cited by applicant]
Sarkis et al., “Resisting Sarcolemmal Rupture: Dystrophin Repeats Increase Membrane-Actin Stiffness”, The FASEB Journal, 2013, pp. 359-367, vol. 27.
[cited by applicant]
Sarkis et al., “Spectrin-Like Repeats 11-15 of Human Dystrophin Show Adaptations to a Lipidic Envrionment”, The Journal of Biological Chemistry, 2011, pp. 30481-30491, vol. 286, No. 35.
[cited by applicant]
Sheetz et al., “Continuous Membrane-Cytoskeleton Adhesion Requires Continuous Accommodation to Lipid and Cytoskeleton Dynamics”, Annu. Rev. Biophys. Biomol. Struct., 2006, pp. 417-434, vol. 35.
[cited by applicant]
Shin et al., “A Simplified Immune Suppression Scheme Leads to Persistent Micro-Dystrophin Expression in Duchenne Muscular Dystrophy Dogs”, Human Gene Therapy, 2012, pp. 202-209, vol. 23.
[cited by applicant]
Shin et al., “Microdystrophin Ameliorates Muscular Dystrophy in the Canine Model of Duchenne Muscular Dystrophy”, Molecular Therapy, 2013, pp. 750-757, vol. 21, No. 4.
[cited by applicant]
Shin et al., “Recombinant Adeno-Associated Viral Vector Production and Purification”, Methods Mol Biol., 2012, pp. 267-284, vol. 798.
[cited by applicant]
Straub et al., “Animal Models for Musuclar Dystrophy Show Different patterns of Sarcolemmal Disruption”, Cell Biology, 1997, pp. 375-385, vol. 139, No. 2.
[cited by applicant]
Suminaga et al., “C-Terminal Truncated Dystrophin Identified in Skeletal Muscle of an Asymptomatic Boy with a Novel Nonsense Mutation of the Dystrophin Gene”, Pediatric Research, 2004, pp. 739-743, vol. 56, No. 5.
[cited by applicant]
Sun et al., “Overcoming Adeno-Associated Virus Vector Size Limitation Through Viral DNA Heterodimerization”, Nature Medicine, 2000, pp. 599-602, vol. 6, No. 5.
[cited by applicant]
Suzuki et al., “Glycoprotein-Binding Site of Dystrophin is Confined to the Cysteine-Rich Domain and the First Half of the Carboxy-Terminal Domain”, Federation of European Biochemical Societies, 1992, pp. 154-160, vol. 3…
[cited by applicant]
Suzuki et al., “Mammalian a1- and b1-Syntrophin Bind to the Alternative Splice-Prone Region of the Dystrophin COOH Terminus”, The Journal of Cell Biology, 1995, pp. 373-381, vol. 128, No. 3.
[cited by applicant]
Suzuki et al., “Molecular Organization at the Glycoprotein-Complex-Binding Site of Dystrophin”, Eur. J. Biochem., 1994, pp. 283-292, vol. 220.
[cited by applicant]
Topinka et al., “N-Terminal Palmitoylation of PSD-95 Regulates Association with Cell Membranes and Interactions with K+ Channel Kv1.4”, Neuron, 1998, pp. 125-134, vol. 20.
[cited by applicant]
Wang et al., “Adeno-Associated Virus Vector Carrying Human Minidystrophin Genes Effectively Ameliorates Muscular Dystrophy in mdx Mouse Model”, PNAS, 2000, pp. 13714-13719, vol. 97, No. 25.
[cited by applicant]
Wang et al., “Construction and Analysis of Compact Muscle-Specific Promoters for AAV Vectors”, Gene Therapy, 2008, pp. 1489-1499, vol. 15.
[cited by applicant]
Wang et al., “Successful Regional Delivery and Long-Term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies”, Molecular Therapy, 2012, pp. 1501-1507, vol. 20, No. 8.
[cited by applicant]
Yan et al., “Trans-Splicing Vectors Expand the Utility of Adeno-Associated Virus for Gene Therapy”, PNAS, 2000, pp. 6716-6721, vol. 97, No. 12.
[cited by applicant]
Yanai et al., “Palmitoylation of Huntingtin by HIP14 is Essential for Its Trafficking and Function”, Nat Neurosci., 2006, pp. 824-831, vol. 9, No. 6.
[cited by applicant]
Yang et al., “Dystrophin Deficiency Compromises Force Production of the Extensor Carpi Ulnaris Muscle in the Canine Model of Duchenne Muscular Dystrophy”, PLOS One, 2012, pp. 1-7, vol. 7, No. 9.
[cited by applicant]
Yang et al., “Identification of a-Syntrophin Binding to Syntrophin Triplet, Dystrophin, and Utrophin”, The Journal of Biological Chemistry, 1995, pp. 4975-4978, vol. 270, No. 10.
[cited by applicant]
Yoshida et al., “Biochemical Evidence for Association of Dystrobrevin with the Sarcoglycan-Sarcospan Complex as a Basis for Understanding Sarcoglycanopathy”, Human Molecular Genetics, 2000, pp. 1033-1040, vol. 9, No. 7.
[cited by applicant]
Yue et al., “C-Terminal-Truncated Microdystrophin Recruits Dystrobrevin and Syntrophin to the Dystrophin-Associated Glycoprotein Complex and Reduces Muscular Dystrophy in Symptomatic Utrophin/Dystrophin Double-Knockout …
[cited by applicant]
Yue et al., “Safe and Bodywide Muscle Transduction in Young Adult Duchenne Muscular Dystrophy Dogs with Adeno-Associated Virus”, Human Molecular Genetics, 2015, pp. 5880-5890, vol. 24, No. 20.
[cited by applicant]
Zhang et al. “Novel Mini-Dystrophin Gene Dual Adeno-Associated Virus Vectors Restore Neuronal Nitric Oxide Synthase Expression at the Sarcolemma”, Human Gene Therapy (2012) pp. 98-103, vol. 23, No. 1; XP055619093, GB IS…
[cited by applicant]
Zhang et al., “Dual AAV Therapy Ameliorates Exercise-Induced Muscle Injury and Functional Ischemia in Murine Models of Duchenne Muscular Dystrophy”, Human Molecular Genetics, May 15, 2013, pp. 3720-3729, vol. 22.
[cited by applicant]
Zhao et al., “Dystrophin contains multiple independent membrane-binding domains”, Human Molecular Genetics, 2016, pp. 3647-3653, vol. 25, No. 17.
[cited by applicant]
Zhong et al., “Next Generation of Adeno-Associated Virus 2 Vectors: Point Mutations in Tyrosines Lead to High-Efficiency Transduction at Lower Doses”, PNAS, 2008, pp. 7827-7832, vol. 105, No. 22.
[cited by applicant]
Allen et al., “Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca
[cited by applicant]
Amann et al., “A Cluster of Basic Repeats in the Dystrophin Rod Domain Binds F-Actin Through an Electrostatic Interaction”, The Journal of Biological Chemistry, 1998, pp. 28419-28423, vol. 273, No. 43.
[cited by applicant]
Bajanca et al., “In Vivo Dynamics of Skeletal Muscle Dystrophin in Zebrafish Embryos Revealed by Improved FRAP Analysis”, 2015, pp. 1-32.
[cited by applicant]
Banks et al., “The Polyproline Site in Hinge 2 Influences the Functional Capacity of Truncated Dystrophins”, Plos Genetics, 2010, pp. 1-10, vol. 6, No. 5.
[cited by applicant]
Barnabei et al., “Severe Dystrophic Cardiomyopathy Caused by the Enteroviral Protease 2A-Mediated C-Terminal Dystrophin Cleavage Fragment”, Science Translational Medicine, 2015, pp. 1-11, vol. 7.
[cited by applicant]
Bennett et al., “An Adaptable Spectrin/Ankyrin-Based Mechanism for Long-Range Organization of Plasma Membranes in Vertebrate Tissues”, Current Topics in Membranes, 2016, pp. 143-184, vol. 77.
[cited by applicant]
Bok et al., “Lipid-Binding Role of bll-Spectrin Ankyrin-Binding Domain”, Cell Biology International, 2007, pp. 1482-1494, vol. 31.
[cited by applicant]
Bostick et al., “AAV Micro-Dystrophin Gene Therapy Alleviates Stress-Induced Cardiac Death but not Myocardial Fibrosis in > 21-m-Old mdx Mice, an End-Stage Model of Duchenne Muscular Dystrophy Cardiomyopathy”, Journal o…
[cited by applicant]
Bostick et al., “Cardiac Expression of a Mini-Dystrophin That Normalizes Skeletal Muscle Force Only Partially Restores Heart Function in Aged Mdx Mice”, Molecular Therapy, 2009, pp. 253-261, vol. 17, No. 2.
[cited by applicant]
Bunnell et al., “Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in a-Dystrobrevin Null Muscle”, PLOS One, 2008, pp. 1-6, vol. 3, No. 7.
[cited by applicant]
Campbell et al., “Association of Dystrophin and an Integral Membrane Glycoprotein”, Nature, 1989, pp. 259-262, vol. 338.
[cited by applicant]
Chandrasekharan et al., “Introduction of a Human-Specific Deletion in Mouse Cmah Increases Disease Severity in the mdx Model of Duchenne Muscular Dystrophy”, Sci Transl Med., 2010, pp. 1-34, vol. 2, No. 42.
[cited by applicant]
Constantin, “Dystrophin Complex Functions as a Scaffold for Signalling Proteins”, Biochimica et Biophysica Acta, 2014, pp. 635-642, vol. 1838.
[cited by applicant]
Cox et al., “Dp71 can Restore the Dystrophin-Associated Glycoprotein Complex in Muscle but Fails to Prevent Dystrophy”, Nature Genetics, 1994, pp. 333-339, vol. 8.
[cited by applicant]
Crawford et al., “Assembly of the Dystrophin-Associated Protein Complex Does Not Require the Dystrophin COOH-Terminal Domain”, The Journal of Cell Biology, 2000, pp. 1399-1409, vol. 150, No. 6.
[cited by applicant]
Das et al., “Purification and Biochemical Characterization of a Protein-Palmitoyl Acyltransferase from Human Erythrocytes”, The Journal of Biological Chemistry, 1997, pp. 11021-11025, vol. 272, No. 17.
[cited by applicant]
Dewolf et al., “Interaction of Dystrophin Fragments with Model Membranes”, Biophysical Journal, 1997, pp. 2599-2604, vol. 72.
[cited by applicant]
Draviam et al., “Mini-Dystrophin Efficiently Incorporates into the Dystrophin Protein Complex in Living Cells”, Journal of Muscle Research and Cell Motility, 2006, pp. 53-67, vol. 27.
[cited by applicant]
Duan et al., “Expanding AAV Packaging Capacity with Trans-Splicing or Overlapping Vectors: A Quantitative Comparison”, Molecular Therapy, 2001, pp. 383-391, vol. 4, No. 4.
[cited by applicant]
Dunckley et al., “Independent Localization of Dystrophin N- and C-Terminal Regions to the Sarcolemma of mdx Mouse Myofibres In Vivo”, Journal of Cell Science, 1994, pp. 1469-1475, vol. 107.
[cited by applicant]
Einbond et al., “Towards Prediction of Cognate Complexes Between the WW Domain and Proline-Rich Ligands”, FEBS Letters, 1996, pp. 1-8, vol. 384.
[cited by applicant]
Ervasti et al., “Membrane Organization of the Dystrophin-Glycoprotein Complex”, Cell, 1991, pp. 1121-1131, vol. 66.
[cited by applicant]
Fine et al., “Age-Matched Comparison Reveals Early Electrocardiogramand Echocardiography Changes in Dystrophin-Deficient Dog”, Neuromuscul Disord., 2011, pp. 453-461, vol. 21, No. 7.
[cited by applicant]
Fritz et al., “Expression of Deletion-Containing Dystrophins in mdx Muscle: Implicatons for Gene Therapy and Dystrophin Function”, Pediatric Research, 1995, pp. 693-700, vol. 37, No. 6.
[cited by applicant]
Gao et al., “The Dystrophin Complex: Structure, Function, and Implications for Therapy”, Compr Physiol., 2015, pp. 1223-1239, vol. 5, No. 3.
[cited by applicant]
Gardner et al., “Restoration of all Dystrophin Protein Interactions by Functional Domains in Trans Does Not Rescue Dystrophy”, Gene Therapy, 2006, pp. 744-751, vol. 13.
[cited by applicant]
Ghosh et al., “A Hybrid Vector System Expands Adeno-Associated Viral Vector Packaging Capacity in a Transgene-Independent Manner”, Molecular Therapy, 2008, pp. 124-130, vol. 16, No. 1.
[cited by applicant]
Ghosh et al., “Expanding Adeno-Associated Viral Vector Capacity: A Tale of Two Vectors”, Biotechnology and Genetic Engineering Reviews, 2007, pp. 165-178, vol. 24.
[cited by applicant]
Halbert et al., “Efficient Mouse Airway Transduction Following Recombination Between AAV Vectors Carrying Parts of a Larger Gene”, Nature Biotechnology, 2002, pp. 697-701, vol. 20.
[cited by applicant]
Harper et al., “Modular Flexibility of Dystrophin: Implications for Gene Therapy of Duchenne Muscular Dystrophy”, Nature Medicine, 2002, pp. 253-261, vol. 8, No. 3.
[cited by applicant]
Helliwell et al., “A Truncated Dystrophin Lacking the C-Terminal Domains is Localized at the Muscle Membrane”, American Journal of Human Genetics, 1992, pp. 508-514, vol. 50.
[cited by applicant]
Hillier et al., “Unexpected Modes of PDZ Domain Scaffolding Revealed by Structure of nNOS-Syntrophin Complex”, Science, Apr. 30, 1999, pp. 812-815, vol. 284.
[cited by applicant]
Hir et al., “Cholesterol Favors the Anchorage of Human Dystrophin Repeats 16 to 21 in Membrane at Physiological Surface Pressure”, Biochimica et Biophysica Acta, 2014, pp. 1266-1273, vol. 1838, No. 5.
[cited by applicant]
Hoffman et al., “Dystrophin: The Protein Product of the Duchenne Muscular Dystrophy Locus”, Cell, 1987, pp. 919-928, vol. 51.
[cited by applicant]
Hoffman et al., “Is the Carboxyl-Terminus of Dystrophin Required for Membrane Association? A Novel, Severe Case of Duchenne Muscular Dystrophy”, Annals of Neurology, 1991, pp. 605-610, vol. 30, No. 4.
[cited by applicant]
Huang et al., “Structure of a WW Domain Containing Fragment of Dystrophin in Complex with b-Dystroglycan”, Nature Structural Biology, 2000, pp. 634-638, vol. 7, No. 8.
[cited by applicant]
Ipsaro et al., “Structural Basis for Spectrin Recognition by Ankyrin”, Blood, 2010, pp. 4093-4101, vol. 115, No. 20.
[cited by applicant]
Ipsaro et al., “Structures of the Spectrin-Ankyrin Interaction Binding Domains”, Blood, 2009, pp. 5385-5393, vol. 113, No. 22.
[cited by applicant]
Ishikawa-Sakurai et al., “ZZ Domain is Essentially Required for the Physiological Binding of Dystrophin and Utrophin to b-Dystroglycan”, Human Molecular Genetics, 2004, pp. 693-702, vol. 13, No. 7.
[cited by applicant]
Johnson et al., “Identification of New Dystroglycan Complexes in Skeletal Muscle”, PLOS One, 2013, pp. 1-17, vol. 8, No. 8.
[cited by applicant]
Johnson et al., “Proteomic Analysis Reveals New Cardiac-Specific Dystrophin-Associated Proteins”, PLOS One, 2012, pp. 1-12, vol. 7, No. 8.
[cited by applicant]
Judge et al., “Dissecting the Signaling and Mechanical Functions of the Dystrophin-Glycoprotein Complex”, Journal of Cell Science, 2006, pp. 1537-1546, vol. 119.
[cited by applicant]
Judge et al., “Expression of the Dystrophin Isoform Dp116 Preserves Functional Muscle Mass and Extends Lifespan Without Preventing Dystrophy in Severely Dystrophic Mice”, Human Molecular Genetics, 2011, pp. 4978-4990, v…
[cited by applicant]
Jung et al., “Identification and Characterization of the Dystrophin Anchoring Site on b-Dystroglycan”, The Journal of Biological Chemistry, 1995, pp. 27305-27310, vol. 270, No. 45.
[cited by applicant]
Koenig et al., “Detailed Analysis of the Repeat Domain of Dystrophin Reveals Four Potential Hinge Segments That May Confer Flexibility”, The Journal of Biological Chemistry, 1990, pp. 4560-4566, vol. 265.
[cited by applicant]
Lai et al., “a2 and a3 Helices of Dystrophin R16 and R17 Frame a Microdomain in the a1 Helix of Dystrophin R17 for Neuronal NOS Binding”, PNAS, 2013, pp. 525-530, vol. 110, No. 2.
[cited by applicant]
Lai et al., “Dystrophins Carrying Spectrin-Like Repeats 16 and 17 Anchor nNOS to the Sarcolemma and Enhance Exercise Performance in a Mouse Model of Muscular Dystrophy”, The Journal of Clinical Investigation, 2009, pp.6…
[cited by applicant]
Lai et al., “Efficient In Vivo Gene Expression by Trans-Splicing Adeno-Associated Viral Vectors”, Nat Biotechnol., 2005, pp. 1435-1439, vol. 23, No. 11.
[cited by applicant]
Lai et al., “Partial Restoration of Cardiac Function with DPDZ nNOS in Aged mdx Model of Duchenne Cardiomyopathy”, Human Molecular Genetics, Jan. 25, 2014, pp. 3189-3199, vol. 23.
[cited by applicant]
Lai et al., “Synthetic Intron Improves Transduction Efficiency of Trans-Splicing Adeno-Associated Viral Vectors”, Human Gene Therapy, 2006, pp. 1036-1042, vol. 17, No. 10.
[cited by applicant]