title: Effective dystrophin restoration by a novel muscle-homing peptide-morpholino conjugate in dystrophin-deficient mdx mice.
abstract: Antisense oligonucleotide (AO)-mediated splice correction therapy for Duchenne muscular dystrophy has shown huge promise from recent phase 2b clinical trials, however high doses and costs are required and targeted delivery can lower both of these. We have previously demonstrated the feasibility of targeted delivery of AOs by conjugating a chimeric peptide, consisting of a muscle-specific peptide and a cell-penetrating peptide, to AOs in mdx mice. Although increased uptake in muscle was observed, the majority of peptide-AO conjugate was found in the liver. To search for more effective muscle-homing peptides, we carried out in vitro biopanning in myoblasts and identified a novel 12-mer peptide (M12) showing preferential binding to skeletal muscle compared to the liver. When conjugated to phosphorodiamidate morpholino oligomers, ~25% of normal level of dystrophin expression was achieved in body-wide skeletal muscles in mdx mice with significant recovery in grip strength, whereas <2% in corresponding tissues treated with either muscle-specific peptide-phosphorodiamidate morpholino oligomer or unmodified phosphorodiamidate morpholino oligomer under identical conditions. Our data provide evidences for the first time that a muscle-homing peptide alone can enhance AO delivery to muscle without appreciable toxicity at 75 mg/kg, suggesting M12-phosphorodiamidate morpholino oligomer can be an alternative option to current AOs.
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Hong M
authors.initials: HM
authors.lastname: Moulton
authors.affiliation: Department of Cell Biology, Research Centre of Basic Medical Science, Tianjin Medical University, Tianjin, China. Electronic address: haifangyin@tmu.edu.cn.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000172:deficiency / Q000378:metabolism*; D018101:Mice, Inbred mdx; D060172:Morpholinos / Q000737:chemistry*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy*; D020388:Muscular Dystrophy, Duchenne; D016376:Oligonucleotides, Antisense; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D016189:Dystrophin; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides
references.citation: Mol Ther. 2010 Apr;18(4):819-27
references.pmid: 20068555
references.citation: Cell Physiol Biochem. 2009;24(5-6):527-36
references.pmid: 19910693
references.citation: Peptides. 2010 Oct;31(10):1873-7
references.pmid: 20621144
references.citation: Methods Mol Biol. 2012;867:407-14
references.pmid: 22454076
references.citation: J Mol Biol. 2004 Sep 3;342(1):171-82
references.pmid: 15313615
references.citation: Nucleic Acids Res. 2008 Nov;36(20):6418-28
references.pmid: 18842625
references.citation: Cell Physiol Biochem. 2005;16(1-3):127-32
references.pmid: 16121041
references.citation: Mol Ther. 2008 Jan;16(1):38-45
references.pmid: 17968354
references.citation: Ann Rheum Dis. 2013 Jan;72(1):129-35
references.pmid: 22843486
references.citation: Hum Mol Genet. 2008 Dec 15;17(24):3909-18
references.pmid: 18784278
references.citation: Physiol Rev. 2002 Apr;82(2):291-329
references.pmid: 11917091
references.citation: Mol Ther. 2011 Jul;19(7):1295-303
references.pmid: 21505427
references.citation: PLoS One. 2012;7(2):e31937
references.pmid: 22359642
references.citation: Lancet. 2011 Aug 13;378(9791):595-605
references.pmid: 21784508
references.citation: Hum Mol Genet. 2009 Nov 15;18(22):4405-14
references.pmid: 19692354
references.citation: Mol Ther Nucleic Acids. 2013 Sep 24;2:e124
references.pmid: 24064708
references.citation: N Engl J Med. 2011 Apr 21;364(16):1513-22
references.pmid: 21428760
references.citation: Science. 1985 Jun 14;228(4705):1315-7
references.pmid: 4001944
references.citation: Curr Opin Mol Ther. 2001 Jun;3(3):239-43
references.pmid: 11497347
references.citation: Mol Ther. 2003 Aug;8(2):295-305
references.pmid: 12907152
references.citation: Methods Mol Biol. 2011;683:321-38
references.pmid: 21053140
references.citation: Adv Drug Deliv Rev. 2005 Feb 28;57(4):559-77
references.pmid: 15722164
references.citation: Bioconjug Chem. 2007 Jul-Aug;18(4):1325-31
references.pmid: 17583927
references.citation: Nat Biotechnol. 2011 Apr;29(4):352-6
references.pmid: 21297616
references.citation: Am J Pathol. 2012 Aug;181(2):392-400
references.pmid: 22683468
references.citation: Muscle Nerve. 1999 Apr;22(4):460-6
references.pmid: 10204780
references.citation: Nucleic Acids Res. 2007;35(15):5182-91
references.pmid: 17670797